InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Oncology » "Future Aspects of Tumor Suppressor Gene", book edited by Yue Cheng, ISBN 978-953-51-1063-7, Published: April 10, 2013 under CC BY 3.0 license. © The Author(s).

Chapter 6

Polyphenolic Compounds Targeting p53-Family Tumor Suppressors: Current Progress and Challenges

By Nelly Etienne-Selloum, Israa Dandache, Tanveer Sharif, Cyril Auger and Valérie B. Schini-Kerth
DOI: 10.5772/56102

Article top


Overview of p53- or p73-mediated pro-apoptotic effects of polyphenols in cancer cells. Polyphenols likely induce intracellular oxidative stress and DNA damage with subsequent activation of kinases (MAPK, ATM, DNA-PK) responsible for p53 phosphorylation. Simultaneously, and also in response to DNA damage, acetylation of p53 or p73 have been described due to enhanced acetylase activity from p300 and/or to reduced deacetylase activity from SIRT1 or HDAC. In addition, p53 expression has been shown to be under the control of MDM2 as well as MTA1/NuRD, both factors being downregulated by polyphenols. Phosphorylation and acetylation, together with MDM2 inhibition result in p53, and to a less extend, p73 stabilization and sustained expression which activate cell death cascade in cancer cells.
Figure 1. Overview of p53- or p73-mediated pro-apoptotic effects of polyphenols in cancer cells. Polyphenols likely induce intracellular oxidative stress and DNA damage with subsequent activation of kinases (MAPK, ATM, DNA-PK) responsible for p53 phosphorylation. Simultaneously, and also in response to DNA damage, acetylation of p53 or p73 have been described due to enhanced acetylase activity from p300 and/or to reduced deacetylase activity from SIRT1 or HDAC. In addition, p53 expression has been shown to be under the control of MDM2 as well as MTA1/NuRD, both factors being downregulated by polyphenols. Phosphorylation and acetylation, together with MDM2 inhibition result in p53, and to a less extend, p73 stabilization and sustained expression which activate cell death cascade in cancer cells.

Polyphenolic Compounds Targeting p53-Family Tumor Suppressors: Current Progress and Challenges

Nelly Etienne-Selloum1, Israa Dandache1, Tanveer Sharif1, Cyril Auger1 and Valérie B. Schini-Kerth1

1. Introduction

The chemotherapeutic properties of polyphenols have recently received an increasing interest since it has been established that these compounds can modulate each step of the cancer progression process (initiation, proliferation, survival, migration, angiogenesis, and metastasis). Polyphenols are believed to be multi-targets drugs and in the present chapter we will give an overview of recent investigations concerning apoptosis induction by three major compounds, resveratrol, curcumin and epigallocatechin-3-gallate (EGCG) mainly through the regulation of the p53 tumor suppressor pathway. The potential regulation by polyphenols of p53 expression at the transcriptional and post-translational levels has been extensively described. Interestingly, polyphenolic compounds are also able to trigger apoptosis of numerous cancer cells, independently of the p53 status (wild-type, mutated or deficient). Moreover alternative mechanisms supported by recent studies highlight the role of p73, a p53 related tumor suppressor, as another key target for polyphenols. Then the molecular mechanisms involved in tumor suppressors (mainly p53 and p73) expression by polyphenols will be discussed with a specific focus on the role of oxidative stress which is believed to be a key element in polyphenols-induced cancer cells death.

2. Anticancer properties of polyphenols: Chemoprevention and chemotherapy

Polyphenols are natural compounds characterized by a structure containing at least one benzene ring substituted by at least one hydroxyl group. Beside this chemical hallmark, phenolic products currently constitute a large and still expanding complex and heterogeneous family of molecules (more than 8000 phenolic structures currently known) with a great diversity of structure and size ranging from the low molecular weight simple phenols up to the high molecular weight tannins [1-3]. Polyphenols are also one of the largest and most widespread classes of constituents present in plant kingdom and more particularly in plant-derived foods and beverages giving them their color and taste properties. Polyphenols can be structurally divided into two main families: flavonoids and non-flavonoids. Flavonoids are especially abundant in fruits, vegetables, seeds, spices, herbs, tea, cocoa, and wine. The six major subclasses of flavonoids are anthocyanidins (e.g., cyanidin, delphinidin; primary sources: red berries, red cabbages, cherries, grapes, and onions), flavan-3-ols (e.g., catechin, epicatechin, EGCG; primary sources: tea, grapes, cocoa, apples, and red wine), flavanones (e.g., hesperitin, naringenin; primary sources: oranges, lemons, and grapefruits), flavones (e.g., apigenin, luteolin; primary sources: celery, parsley, and thyme), flavonols (e.g., kaempferol, myricetin, quercetin; primary sources: apples, beans, broccoli, and onions), and isoflavonoids (e.g., daidzein, genistein; primary sources: legumes and soy products). Phenolic acids represent a large subclass of non-flavonoid polyphenolic compounds which can be further divided into two main types: benzoic acids (e.g., gallic acid, ellagic acid, vanillic acid; primary sources: tea, red wine, berries, nuts, and herbs) and cinnamic acids (e.g., caffeic acid, chlorogenic acid; primary sources: coffee, berries, plum, and apple). Other important classes of non flavonoids with healthy properties are stilbenes, such as resveratrol (primary sources: red wine, berries and nuts) and curcuminoids such as curcumin the main component of dried turmeric and curry powder [4]. Polyphenols are considered as secondary plant metabolites and have been associated with several functions in plants such as resistance against microbial pathogens and insects, protection against DNA-damaging UV light, reproduction, nutrition and growth [3]. In parallel to their protective properties in plants, polyphenols have long been regarded as a pool of bioactive natural products with potential benefits for human health. Plant extracts, herbs and spice containing these compounds have been used for thousands of years in traditional medicines. Nowadays, plant polyphenols enjoy an ever-increasing recognition not only by scientific community but also, and most remarkably, by the general public because of their presence and abundance in fruits, seeds, vegetables and derived foodstuffs and beverages, whose regular consumption has been claimed to be beneficial for human health [3, 5]. Indeed, epidemiological and experimental studies have shown the potential of polyphenols or polyphenolic nutritional sources in reducing the risk of chronic diseases such as cardiovascular diseases [6-10] and cancers [10-14], as well as the risk of degenerative diseases [10, 15, 16]. Altogether these observations led to the current nutritional recommendations to eat five servings of fruits and vegetables per days in order to keep healthy.

A wealth of data, including epidemiological and animal studies, has described the chemopreventive and anticancer properties of polyphenolic compounds, such as resveratrol, curcumin or tea catechins, or polyphenol-rich nutritional sources [13, 14, 17-19]. Nonetheless, recent investigations have highlighted additional mechanisms responsible for direct anti-proliferative and chemotherapeutic properties of polyphenols. Indeed, these compounds can interfere with the initiation, as well as the progression of cancer through the modulation of different cellular events, such as cell cycle arrest by decreasing cyclins or apoptosis induction through cytochrome c release, activation of caspases and down- or up-regulation of Bcl-2 family members, and inhibition of survival/proliferation signals (AKT, MAPK, NF-κB, etc.). Furthermore, they play an important role in inflammation (COX-2, TNF secretion, etc.), as well as in suppression of key proteins involved in angiogenesis and metastasis [13]. Importantly, it has been established that tumor suppressors like p53 and its analogs are key molecular targets of polyphenols responsible for their pro-apoptotic effect in human and animal cancer models. Here we provide an overview of the molecular mechanisms involved in p53 family proteins modulation by three major and well characterized polyphenolic compounds, resveratrol, curcumin and EGCG.

3. p53 family proteins are chemotherapeutic targets of polyphenols

Since the discovery of p53 in 1979 [20-22] numerous studies have been conducted related to its functions in response to stress and its regulatory mechanisms. p53 is a sequence-specific nuclear transcription factor that binds to defined consensus sites within DNA as a tetramer and represses transcription of a set of genes involved in cell growth stimulation, while activating a different set of genes involved in cell cycle control, like p21. It causes growth arrest providing a window for DNA repair or elimination of cells with severely damaged DNA strands. In some conditions, p53 activation triggers the transcription of pro-apoptotic genes such as Bax or PUMA, as well as the repression of anti-apoptotic genes like survivin [23]. Moreover, p53 can induce transcription-independent apoptosis. This mechanism involves early p53 translocation to mitochondria where it binds to Bcl-2 family proteins, such as Bax, Bak and Bcl-XL, activating cytochrome c release and caspases cascade [24]. Undoubtedly p53 exerts major anti-neoplastic effects and is considered actually as the “guardian of the genome” [25]. Tumor suppressive capabilities of p53 are related to a coordinated regulatory circuit that monitors and responds to a variety of stress signals, including DNA damage, abnormal oncogenic events, telomere erosion and hypoxia [26]. Importantly, in unstressed cells, p53 is latent and is maintained at low level by targeted ubiquitin-mediated degradation related to its interaction with ubiquitine ligases, mainly MDM2 [27]. Regarding the “guardian” functions of p53, mutations of p53 gene or disruptions of p53 coordination such as post-translational inactivation, can disturb the normal physiological balance, and lead to cancer if genome disarrangement reachs a critical value [28]. Indeed, low level of functionnal p53 is a common characteristic of cancer from several localizations including lung, colon, rectum, breast, brain, bladder, stomac, prostate, ovary, liver or lymphoid organs [29]. Somatic p53 missense inactivating mutations are found in approximately 50% of human cancers [30] and this inactivating mutations render the mutant p53 protein unable to carry out its normal function, that is, transcriptional transactivation of downstream target genes that regulate cell cycle and apoptosis [31-33]. On the other hand, p53 pathway can be also inactivated in wild-type (WT) p53-carrying tumors via indirect mechanisms such as MDM2 amplification leading to p53 destabilization [34, 35].

Recently, cDNAs with strong homologies to p53 have been identified and their products were termed p63 and p73 [36-38]. Both proteins are structurally similar and functionally related to p53, and consequently the entire p53 family may be regarded as a unique signalling network controlling cell proliferation, differentiation and death. Interestingly, in contrary to p53, the role of the other two p53-related proteins in tumor suppression is less obvious, since they are rarely deleted or mutated in cancer, and the respective knockout mice die tumor-free from developmental defects [39-41]. However, increasing number of evidences suggest that both p63 and p73 have a role in tumor suppression. Indeed, different studies indicated that TAp73 and TAp63, the transcriptionally active isoforms, can induce cell cycle arrest, senescence, DNA repair, and apoptosis in response to chemotherapeutic drugs, independently of p53 [42-45]. In addition, even if not mutated, p63 and p73 can be aberrantly expressed in cancer. More particularly, the dominant negative and transcriptionally inactive isoforms ∆Np63 and ∆Np73 are frequently overexpressed in a wide range of tumors, in which they are associated with poor prognosis [46]. Actually, the imbalance in the TAp73/∆Np73 may be more critical for tumorigenesis and response to chemotherapy than mutations [47]. In summary, despite their differences, the three members of the p53 family may be considered as therapeutic targets for cancer management.

Many in vitro studies as well as few in vivo studies have shown that resveratrol, curcumin and EGCG, as well as nutritional sources of polyphenols induce overexpression of wild-type p53 (Table 1-4). The p53-related anticancer properties of these three isolated molecules have been extensively evaluated but other polyphenolic compounds such as genistein, luteolin, quercetin, and wogonin have been shown also to upregulate wild-type p53 protein in several cancer cell lines [48-51]. The polyphenol-induced stabilization and expression of wild-type p53 is often associated with a G1 or G2/M phase cell cycle arrest together with transcriptional regulation of target genes such as p21, Bax, PUMA and apoptosis induction [52-56]. The key role of p53 in polyphenol-induced anticancer properties is supported by studies indicating that p53 downregulation counteracts apoptosis triggered by natural products. Indeed, p53 silencing by siRNA abrogate the cytotoxic effect of curcumin in chondrosarcoma cells [57] and genetic invalidation of p53 by shRNA leads to inhibition of EGCG plus luteonin-induced apoptosis of lung cancer cells [58]. In addition, EGCG fails to induce significant cytotoxic effect in p53-null PC-3 prostate cancer cells, but forced expression of p53 in such cell line leads to sensitization to the polyphenolic compound [53]. Indeed, in the later study EGCG induces p53 phosphorylation on Serine 15 and upregulation of p53 and p21 expression together with cell cycle arrest and apoptosis. However the key role of p53 in the anticancer properties of polyphenols is still controversial, especially for curcumin, since many studies have shown its anti-proliferative properties in several p53-mutated or p53-null cancer cell lines (Table 2). For instance, curcumin has significant anti-proliferative effects in two p53-mutated human glioblastoma cell lines, indicating alternative and p53-independent pathway involved in such anticancer properties [59]. Similarly, curcumin reduces glioblastoma cells viability irrespective of p53 mutational status [60]. In this study, curcumin-induced cancer cell death was associated with caspase-3 activity in p53-wild-type cells, but not in p53-mutated cells, indicating that polyphenols can trigger p53- and caspases-independent cell death. p53-independent anticancer properties of polyphenols have been also described in many other cancer cells [61-67]. Interestingly, curcumin reduces the expression of the mutated form of p53 in MDA-MB-231 breast cancer cells together with cell cycle arrest [68], suggesting that a polyphenol-dependent regulatory process can also modulate the expression of a non-functional tumor suppressor. However, despite potential apoptosis induction by polyphenols in absence of functional p53 protein, its wild-type expression makes cancer cells more sensitive to pro-apoptotic effects of polyphenols. Recently, Ferraz da Costa et al. have demonstrated that transient transfection of wild-type p53 in human non-small lung carcinoma cell line H1299 (p53 negative) dramatically increased susceptibility to resveratrol-induced apoptosis [69]. Altogether these data indicate that p53 participates to the cytotoxic effect of polyphenols but also that alternative pathways might be involve in their anticancer properties.

One of this alternative pathway might involve Egr-1, an immediate early-response gene induced by stress, injury, mitogens, and differentiation [70]. Egr-1 regulates the expression of genes involved in the control of growth and apoptosis by transactivating many proteins including p21. One study has shown that transcription of the p21 gene is activated by Egr-1 independently of p53 but under the control of MAPKs in response to curcumin treatment in U-87MG human glioblastoma cells [71]. In addition, the apoptotic effect of resveratrol in colorectal cancer cells as well as EGCG-mediated cytotoxicity in pulmonary cancer cells are also associated with Egr-1 upregulation [72, 73].

Alternatively to p53, its functionally related proteins p63 and p73 might represent targets for polyphenols. Nevertheless only few data are available concerning a potential regulatory effect of polyphenolic compounds on p63 and p73 (Table1-4). Different flavones (luteolin, apigenin, chrysin) and flavonols (quercetin, kaempferol, myricetin) are able to induce cytotoxicity in p53-mutated oesophageal squamous carcinoma cells together with upregulation of p63 and p73 [74]. Similarly, EGCG induces selective apoptosis in multiple myeloma cells with overexpression of p63 and p73 without any change in the p53 expression level [75], as well as overexpression of p73 in p53-mutated T-lymphocyte leukemic cells [76]. As previously mentioned, different isoforms of p73 have been described and quercetin has been shown to control the subcellular localization of the dominant negative isoform ∆Np73 in melanoma cells expressing wild-type p53. In this model, quercetin caused redistribution of ΔNp73 into the cytoplasm and nucleus, which has been associated with increased p53 transcriptional activity and apoptosis [47, 77]. Beside isolated compounds, more complex sources of polyphenol such as red wine polyphenolic extract or berries-derived product can also modulate p53 and/or p73 expression level, in vitro and in vivo (Table 4) [78-81]. Interestingly, a synthetic analogue of curcumin increases p73 expression level in two distinct p53-wild-type pancreatic cancer cell lines, BxPC-3 and Colo-357 together with upregulation of pro-apoptotic effector Bax and simultaneous downregulation of the anti-apoptotic protein Bcl-2 [82]. Curcumin itself has been shown to stimulate p53 and also p73 expression in p53-mutated C33A cervical cancer cells [83]. Moreover, EGCG upregulates transcriptional target of p53, in a p53-independent but p73-dependent manner in mouse embryonic fibroblasts [84]. These data suggest that independently of the p53 status (wild-type, mutated or deleted), p73 seems to be involde in the anticancer effect of polyphenolic compounds. Many others studies have shown the potential of polyphenols to induce apoptosis of cancer cells in a p53-dependent but also a p53-independent manner (Table 1-4). In summary data concerning the role of tumor suppressors in the polyphenol-induced anticancer effects are inconsistent, probably dependent on the cell type, and consequently remain controversial. Moreover, the molecular mecanisms responsible for p53-family tumor suppressors regulation by polyphenols are only partially elucidated. However some evidences indicate that polyphenols might modulate p53 or p73 expression as well as their stabilization which are under the control of phosphorylation and acetylation levels.

Resveratrol media/image1.png media/image2.png
Cancer modelDescribed effects on TSG (p53/p73)References
Prostate cancer cells (LNCaP, DU145, p53-mutated CWR22Rv1, p53-null PC-3)- No change in p53 mRNA, increased expression of p53-p(ser15) and/or p53-ac(lys382) and total p53 protein
- p53 translocation to mitochondria
- cell cycle alteration and apoptosis induction maintained in p53-mutated cancer cells
- potentiation of radiation–induced p53 expression in p53-mutated cancer cells
[135, 158, 164, 165, 175, 176]
Ovarian carcinoma cells (OVCAR-3)- nuclear accumulation of p53-p(Ser15)[110]
Breast cancer cells (MCF-7, p53-mutated MDA-MB-231, p53-mutated MDA-MB-435)- increased expression of p53-p(ser15), p53-p(ser20), p53-p(ser392) and p53-ac(lys382/lys373)[177-180]
- no change in total p53 protein expression, p53-independent apoptosis [178, 181]
- increased expression of p53 mRNA and total protein[182-184]
- no change in p53 mRNA[185]
- p53-independent cytochrome c release[181]
- increased p53-dependent transcriptional activity[50]
Colon cancer cells (HCT116, p53-null HCT116)- increased p53-p(ser15) expression
- resveratrol-induced senescence is p53 dependent
Pancreatic cancer cells (capan-2, colo357)- upregulation and nuclear accumulation of p53 in both cell line (restoration of wild-type expression) [186]
Glioblastoma cells (A172, p53-mutated T98G)- no change in p53 mRNA[187]
Hepatocellular carcinoma cells (HepG2)- no change in p53 mRNA[185]
Osteosarcoma cells (U-2 OS)- increased p53-p(ser15) and p53-p(Ser37) expression[188]
Lung adenocarcinoma cells (A549)- increased p53-p(ser15) and p53-p(Ser37) expression[188]
Head and neck squamous cancer cells (UMSCC-22B)- increased p53-p(ser15) and total p53 expression[109]
Cervical cancer cells (HeLa)- increased p53-ac(lys373) and total p53 expression[185]
Hodgkin lymphoma cells (L-428)- increased p53-p(ser15) expression[129]
Follicular lymphoma cells (LY8)- increased p53-p(ser15) and total p53 expression[190]
Acute lymphoblastic leukemia cells (MOLT-4)- increased p53-p(ser15) expression[189]
Neuroblastoma cells (B65, NUB-7)- increased p53-p(ser15) and total p53 expression
- nuclear translocation of p53
[94, 132]
DMBA-TPA-induced mouse skin tumor ; DEN-induced rat hepatocellular carcinoma- increased p53-p(ser15) and total p53 expression[18, 191, 192]
- increased wild-type p53 and decreased mutated-p53 expression[193]

Table 1.

p53 family-related anticancer properties of resveratrol

[i] - Cancer cell lines express wild-type p53 except where otherwise stated; ac(lys.)=acetylated lysine, p(ser.)=phosphorylated serine

Curcumin media/image3.png media/image4.jpeg
Cancer model Described effects on TSG (p53/p73) References
Breast cancer cells (MCF-7, p53-mutated MDA-MB-231, p53-mutated SkBr3)- increased expression of p53-p(ser15), no change or increased expression of total p53
-decreased expression of mutated p53
[68, 178, 194-197]
Cervical cancer cells (p53-mutated C33A, Caski)-increased expression of p53 and p73[83, 198]
Ovarian cancer cells (HEY, OVCA429, p53-mutated OCC1, p53-null SKOV3, CaOV3, Ho-8910)-p53-independent cell death[106]
-increased expression of p53-p(ser15)
-increased expression of p53
[107, 199, 200]
Prostate cancer cells (LNCaP, p53-null PC3)-increased expression of p53-p(ser15),p53-ac(lys) and total p53 protein
-p53-independent cell death
-p53 translocation to mitochondria
[95, 100, 201]
Bladder cancer cells (p53 mutated-T-24 and AY-27)-no change or increased expression of p53 [202, 203]
Erhlich Ascite carcinoma cells-increased expression of p53-ac(lys373) and total p53[120]
Colorectal cancer cells (LoVo, HCT116, p53-null HCT116, p53-mutated HT29, p53-mutated Colo205)-increased expression of total p53[52, 204]
-increased expression of p53-p(ser15), p53-p(ser33) and total p53[64]
-no change in p53 expression[173]
-increased expression of p53-p(ser15)
-decreased or unchanged expression of mutated p53
[156, 205]
-cell cycle arrest, senescence and autophagy independent of p53 expression
-cytochrome c release independent of p53 expression
-increased expression of total p53
[206, 207]
Colitis-associated colorectal cancer in mice-no change in p53 expression[17]
Acute lymphoblastic leukemia cells (B6p210, T315I)-increased expression of total p53[208]
Chondrosarcoma cells and xenograft in nude mice (JJ012)-increased expression of total p53 in vitro and in vivo
-p53-dependent apoptosis
Melanoma cells (MMRU, p53-mutated PMWK, B16BL6)-no change in p53 expression[209, 210]
Glioblastoma cells (C6, U-87MG, p53-mutated U138MG and U251, DBTRG, T98G, T67)-p53-independent cell death
-unchanged or increased expression of p53
[60, 71, 163, 211, 212]
Neuroblastoma cells (SK-N-AS, NUB-7, p53-mutated SK-N-BE(2))-p53-independent cell death
-nuclear translocation of p53
[65, 94]

Table 2.

p53 family-related anticancer properties of curcumin

[i] - Cancer cell lines express wild-type p53 except where otherwise stated; ac(lys.)=acetylated lysine, p(ser.)=phosphorylated serine

Epigallocatechin-3-gallate (EGCG) media/image5.png media/image6.png
Cancer modelDescribed effects on TSG (p53/p73)References
Breast Cancer cells (MCF7, p53-mutated MDA-MB-468)-increased expression of p53-p(ser15) and total p53
-p53-independent cell death
[213, 214]
Prostate cancer cells (LNCaP, p53-null PC-3, p53-expressing PC-3, PC3-ML, p53-mutated DU-145)-increased expression of p53-p(ser6), p53-p(ser15), p53-p(ser20), p53-p(ser37), p53-p(ser392) , p53-ac(lys373), p53-ac(lys382) and total p53
-p53-dependent and independent cell death
-increased expression of p73
[53, 66, 89, 139, 140, 170, 215]
PC3-ML cells (prostate cancer) xenograft in mice-increased expression of p53 and p73 (synergistic effect with paclitaxel and docetaxel)[170]
Cervical cancer cells (Hela)-increased expression of p53[216]
Ovarian cancer cells (PA-1, p53-null SKOV3, p53-mutated OVCAR-3)-p53-independent cell death[217]
Hepatocellular carcinoma cells (HepG2, p53-null Hep3B)-increased expression of p53
-p53-independent cytotoxicity
[218, 219]
Colorectal cancer cells ( HCT116, p53-mutated HT-29)-increased expression of p53[55, 155, 157]
Head and neck squamous carcinoma cells (KB, Hep2, Tu686, 686NL, Tu212, Tu177, p53-null M4e)-increased expression of p53-p(ser15) and p53-p(ser37),
-decreased expression of p53-p(ser6), p53-p(ser392)
-unchanged or increased expression of p53
-p53-dependent cytotoxicity
[101, 172, 220]
Head and neck squamous cell carcinoma syngenic mouse model (SCC VII/SF cells xenograft)-increased in vivo expression of p53-p(ser15)[101]
Lung cancer cells (A549)-increased expression of p53-p(ser15) and total p53
-absence of p73 expression
-p53-dependent activation of caspases 3/7
Fibrosarcoma cells (HT-1080)-increased expression of p53[222]
Sarcoma xenograft (S180)-increased in vivo expression of p53[90]
Multiple myeloma cells (INA6)-increased expression of p63 and 73, unchanged expression of p73[75]
T lymphocyte leukemic cells (p53-mutated Jurkat, HuT-102, C91-PL, p53-mutated CEM)-increased expression of p73
-increased expression of p53
[76, 223]

Table 3.

p53 family-related anticancer properties of EGCG

[i] - Cancer cell lines express wild-type p53 except where otherwise stated; ac(lys.)=acetylated lysine, p(ser.)=phosphorylated serine

Polyphenolic source Cancer model p53- and p73-related effects References
Grape-derived products (red wine, grape seed extract)C26 colorectal cancer cells xenograft in mice-increased expression of p53 and p73[78]
Human colorectal cancer cells (LoVo, p53-mutated HT29, P53-mutated SW480)-p53-independent apoptosis[224]
Oral squamous carcinoma cells (SCC-25, p53-mutated OEC-MI)-p53-independent cytotoxicity[225]
Leukemia cells (p53-mutated Jurkat)-increased expression of p73 [80]
Teratocarcinoma cells (P19)-increased expression of p53 [174]
Prostate cancer cells (LNCaP, p53-mutated DU145)-increased expression of p53-p(ser15) and total p53 [226]
Black and green teaDMBA-induced mammary tumor in rat-increased expression of wild-type p53 and decreased expression of mutated-p53 [227]
3,4-benzopyrene-induced lung carcinoma in rat-increased expression of p53[228]
Ehrlich’s ascites carcinoma cell xenograft in mice-increased expression of p53 [229]
Oral cells from smoker and non-smoker subjects-increased expression of p53[230]
Patients with high-risk oral premalignant lesions-no association between p53 expression and clinical response[231]
Prostate cancer cells (LNCaP, p53-null PC3)-increased expression of p53-ac(lys373), p53-ac(lys382) and total p53
-p53-independent apoptosis
[139, 140]
Colorectal cancer cells (LoVo, p53-mutated HT29)-p53-independent cytotoxicity[232]
Berry-derived products (aronia juice, strawberry extract)Leukemia cells (p53-mutated Jurkat)-increased expression of p73[79]
Breast cancer cells (p53-mutated T47D)-increased expression of p73[81]

Table 4.

p53 family-related anticancer properties of polyphenolic sources

[i] - Cancer cell lines express wild-type p53 except where otherwise stated; ac(lys.)=acetylated lysine, p(ser.)=phosphorylated serine

4. Polyphenols as regulator of p53 expression and localization

Under physiological conditions, the transcriptional activity of p53 is downregulated by three different ways: i) ubiquitin-mediated proteasomal degradation mainly through the action of mouse double minute protein (MDM2), ii) nuclear export leading to a decrease in nuclear level, or iii) transcriptional repression of chromatin. MDM2 is an ubiquitin E3 ligase considered as an oncoprotein because of its activity in promoting p53 ubiquitination and proteasomal degradation. Moreover MDM2 binds to the NH2 terminus of p53 and blocks its transactivational activities [27]. Interestingly, MDM2 promotes also cell cycle progression independently of p53 for instance by modulating the activity of p21 [85]. Then MDM2 itself represents a potential target for new drug with chemotherapeutic properties including polyphenolic compounds [86]. Indeed, curcumin has been identified as an inhibitor of MDM2 expression (Figure 1) in vitro and in vivo in p53-null and p53-wild-type human prostate cancer cells and this inhibitory effect seems to be related to the inhibition of the PI3K/mTOR pathway [87]. In addition, the curcumin analog EF24, which displays higher potency, increases phosphorylation of p53 together with downregulation of MDM2, which likely leads to p53 overexpression and cytotoxicity in hepatocellular carcinoma cells [88]. Similarly, EGCG reduces MDM2 expression in prostate cancer cells [89], but not in sarcoma cells [90]. Data concerning the effect of resveratrol on MDM2 expression are more controversial since upregulation or downregulation have been observed in different cancer models [91, 92].

As mentioned previously, p53 activity depends upon its expression level but also its subcellular localization. Indeed, p53 displays direct pro-apoptotic effects related to mitochondrial translocation and this pathway works in synergy with transcriptional activation function of p53 dependent upon its nuclear translocation [24, 93]. Therefore, the control of p53 subcellular localization might interfere with p53-mediated cell death. For instance, treatment of neuroblasma cells by either curcumin or resveratrol transiently upregulated p53 expression and induced nuclear translocation of p53, followed by induction of p21 and Bax expression associated with apoptosis [94]. In addition curcumin increases p53 and Bax expression in mitochondrial fraction under the control of the PI3K/Akt pathway in prostate cancer cells followed by caspase-dependent apoptosis [95]. Altogether, these data indicate that polyphenols are able to control not only p53 expression, but also its localization and therefore its pro-apoptotic activity in cancer cells. However, other post-translational regulatory effects of polyphenols have been also described and related to phosphorylation and acetylation of the tumor suppressor.


Figure 1.

Overview of p53- or p73-mediated pro-apoptotic effects of polyphenols in cancer cells. Polyphenols likely induce intracellular oxidative stress and DNA damage with subsequent activation of kinases (MAPK, ATM, DNA-PK) responsible for p53 phosphorylation. Simultaneously, and also in response to DNA damage, acetylation of p53 or p73 have been described due to enhanced acetylase activity from p300 and/or to reduced deacetylase activity from SIRT1 or HDAC. In addition, p53 expression has been shown to be under the control of MDM2 as well as MTA1/NuRD, both factors being downregulated by polyphenols. Phosphorylation and acetylation, together with MDM2 inhibition result in p53, and to a less extend, p73 stabilization and sustained expression which activate cell death cascade in cancer cells.

5. Polyphenols as regulator of p53 phosphorylation

Phosphorylation of serine/threonine residues are essential for stabilization and activation of p53, the most extensively studied being serine 15 (Ser 15). These phosphorylation sites are mainly concentrated in the N-terminal transactivation domain and in the C-terminal regulatory domain [96]. Recent data about p53 phosphorylation induced by resveratrol, curcumin or EGCG, in vitro and in vivo, are summarized in Tables 1, 2 and 3 as well as in Figure 1. The DNA damage is one of the main signals relayed to p53 subsequently activated by phosphorylation at serine residues that are the target of ataxia-telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR) and DNA-dependent protein kinase (DNA-PK) [97]. The DNA damage response could be activated by chemotherapeutic drugs, UV or oxidative stress [98, 99], but activation of this pathway by polyphenols remains controversial. Watson et al. investigated the pro-apoptotic effect of curcumin which is similar in p53+/+ (wild-type) and p53-/- (knockout) HCT116 colorectal cancer cells. Moreover, they demonstrated the ability of this polyphenol to induce up regulation of p53-p(Ser 15) and total p53 without any change in the expression level of ATM, ATR or DNA-PK. In contrast, curcumin enhances p38, JNK and ERK1/2 phosphorylation in both p53+/+ and p53-/- HCT116 cell lines; this suggests that the cytotoxic effects of curcumin are independent of the DNA-damage/ATM/ATR/DNA-PK pathway but associated with Mitogen-Activated Protein Kinases (MAPKs) activities [64]. On the other hand, treatment of LNCaP prostate cancer cells or HCT116 colorectal cancer cells with curcumin induces the phosphorylation of ATM, histone H2AX (a marker of DNA damage) and p53 at Ser 15 together with increased expression of p53, suggesting p53 activation through the DNA damage/ATM pathway [52, 100]. The importance of ATM in polyphenols-induced cytotoxicity is also supported by recent data showing that EGCG lose the ability to trigger p53 phosphorylation at Ser 15 in absence of ATM [101]. In addition, genistein induced p53 phosphorylation at Ser 6, 9, 15, 20, 46 and 392 in the ATM-proficient human lymphoblastic cell lines, but not in ATM-deficient cell lines, indicating a key role of ATM kinase activity for polyphenol-induced p53 activation [102]. Moreover, stimulation of the ATM/p53 pathway by polyphenols like resveratrol has been shown to also participate in senescence of cancer cells [103]. On the other hand, quercetin strongly induced DNA-PK expression, p53 phosphorylation and apoptosis in melanoma cells, suggesting that other kinases might be activated by polyphenols [77].

Alternatively, MAPKs such as ERK1/2, p38 or JNK have been involved in p53 activation and phosphorylation [104, 105]. Therefore, the potential MAPKs/p53-dependent activation of apoptosis by polyphenols has been investigated. As previously mentioned, curcumin induces phospho-p38, phospho-ERK1/2 and phospho-JNK in colorectal as well as ovarian cancer cells [64, 106, 107]. In addition, it has been shown that resveratrol- or luteolin-induced apoptosis depends on the activities of ERK1/2, JNK and p38 kinase which target p53 phosphorylation at Ser 15 [49, 108]. An alternative pathway which implicates cyclooxygenase (COX)-2 activity and expression has been decribed by Lin et al. They have shown that resveratrol-induced apoptosis of human head and neck squamous cancer cells or human ovarian carcinoma cells is associated with p53 phosphorylation at Ser 15 and that both processes are downregulated by pERK1/2 and COX-2 specific inhibitors [109, 110]. Recent investigations indicate that ERK and p53 regulate each other and that ATM controls their interaction [104]. Therefore polyphenols might likely trigger p53 activation through ATM and MAPKs complementary pathways.

6. Polyphenols as regulators of p53 and p73 acetylation

Functions of p53 and p73 are also regulated by acetylation on different lysine (Lys) residues. These posttranslational covalent modifications occur in response to DNA damage in the close vicinity of the oligomerization domain. The main Histone Acetyl Transferases (HATs) responsible for these modifications include p300, CREB-Binding Protein (CBP), P300/CBP-Associated Factor (PCAF) and Tat-Interactive Protein of 60 kDa (TIP60) [38]. As a consequence of its acetylation, p53 is stabilized by excluding ubiquitination on the same site and acetylation also promotes p53 transcriptional activity [96]. In comparison to p53, only few data are available concerning p73 interaction with HAT and acetylation. It has been established that p300 can acetylate p73 in response to DNA damage, but p300 can also behave as a co-activator of p73 independently of its HAT activity [111]. Importantly, the level of p53 or p73 acetylation seems to be a major way of regulation for the tumor suppressors function since deacetylated p53 and p73 are compromised in their ability to induce cell cycle arrest and apoptosis [91, 112].

The transcriptional coactivator p300 is a large multidomain protein that possesses histone acetyl-transferase ability [113]. Together with its homolog CBP, p300 mediate transcription through binding to transcriptional activators such as JUN, E1A, NF-κB, as well as to the p53 family members and they have been involved in human diseases including cancers [114]. Recent studies indicate that the transcriptional activity of p53 and p73 in response to genotoxic stress is regulated by its interaction with p300 [115-117]. Indeed, it has been established that interaction between p73 and p300 acetyl-transferase promotes first p73 stability and then its transcriptional activity.

Narayanan et al., have suggested that resveratrol-induced apoptosis of prostate cancer cells is mediated by transcriptional activation of p300 which subsequently acetylates and stabilizes p53 [118]. Similarly in breast cancer cells, resveratrol enhanced p300 expression and interaction with the phosphorylated form of p53 by a MAPK-dependent mechanism [119]. Interestingly, p53-p300 interaction fails to occur in doxorubicin-resistant cells, but curcumin pre-treatment could restore this interaction. Consistently, curcumin also restored drug-induced p53 acetylation (lysine 373) and p53-dependent transcription of Bax, PUMA, and Noxa in resistant cells leading to their apoptosis [120]. Therefore, polyphenols-induced acetylation of p53 by p300 might represent a key molecular mechanism for the cytotoxic properties of these natural compounds in cancer cells including chemoresistant cells (Figure 1).

Acetylation level of tumor suppressors is dependent upon the balance between acetylation and deacetylation reactions. Indeed, deacetylation of p53 or p73 by SIRT1 (silent information regulator 1), a member of the sirtuin Histone DeACetylase (HDAC) class III family, prevents p53-mediated transactivation of cell cycle inhibitor p21 and pro-apoptotic factor Bax, allowing promotion of cell survival after DNA damage and ultimately tumorigenesis [121]. Members of the Silent Information Regulator family (SIRT or sirtuins) are evolutionary conserved NAD-dependent protein deacetylases and adenosine diphosphate (ADP)-ribosylases. There are seven identified isoforms (SIRT1-7) that differ in their subcellular localization (cytoplasmic, mitochondrial or nuclear), substrate specificities and functions [122]. The founding member of this class of deacetylases, SIRT1 (homolog of yeast silent information regulator, Sir2), is the most widely studied sirtuins. SIRT1 has been associated with aging processes as well as a variety of human diseases such as metabolic syndrome, inflammation, neurodegeneration and more recently cancer [123, 124]. SIRT1 can deacetylate a variety of histones as well as a number of non-histone substrates, the first identified of these non-histone substrates being p53 (Lys 382-p53). The SIRT1 activity on p53 results in repression of p53-dependent apoptosis in response to DNA damage and oxidative stress [125, 126]. SIRT1 deacetylates also other tumor suppressors such as p73 [91]. Then SIRT1 has been considered as an oncogenic protein because of its role in inactivating tumor suppressors such as p53, p73 but also PTEN [127], and/or activating other oncogenic proteins like N-Myc [128]. Nevertheless, the oncogenic potential of SIRT1 has been controversial and, depending on the context, SIRT1 might also act as a tumor suppressor [122]. However, inhibition of the oncogenic potential of SIRT1 is likely able to induce apoptosis by counteracting the deacetylation of p53 or p73 and other key factors such as FOXO3a [91, 125, 129].

In 2003, resveratrol was the top hit in a screen designed to identify activators of sirtuin enzymes [130] and was subsequently shown to extend lifespan in yeast. However following experiments led to confusing data suggesting that resveratrol might not be a direct activator of SIRT1 [131]. Regardless of the controversy about its mode of action, resveratrol has been confirmed to have numerous health benefits, including anticancer properties. Nevertheless, the role of SIRT1 in the anti-proliferative and pro-apoptotic effects of resveratrol on cancer cells is still unclear. Indeed, in neuroblastoma cells, resveratrol-induced apoptosis was associated with a reduced expression of SIRT1 as well as up-regulation of the acetylated and active form of p53, but the pre-treatment of cancer cells with SIRT1 enzymatic inhibitors such as sirtinol or nicotinamide has no cytotoxic effect suggesting that resveratrol-induced apoptosis is independent of SIRT1 activity [132]. In the opposite, siRNA-mediated downregulation of SIRT1 in lymphoma cells decreased the resveratrol-induced apoptosis, indicating in this case a critical role of SIRT1 in polyphenol-mediated cancer cell death [133]. Interestingly, Frazzi et al., have recently described anti-proliferative effect of resveratrol associated with downregulation of SIRT1 expression and activity together with upregulation of acetylated-Lys 373-p53, the active form of p53, and total p53 overexpression [129]. All together, these data suggest that, in the context of cancer cells, resveratrol might be an inhibitor, instead of an activator, of SIRT1 functions (Figure 1). However, only few data are available concerning potential regulation of SIRT1/p53 pathway by other polyphenolic compounds [134]. Therefore additional investigations are needed to further understand the role of SIRT1 in polyphenols-mediated anticancer effects.

On the other hand, resveratrol has been shown to enhance p53 acetylation and apoptosis in prostate cancer cells through alternative pathways. Indeed, resveratrol caused down-regulation of MTA1 protein, leading to destabilization of MTA1/NuRD complex thus allowing acetylation/activation of p53 [135]. Metastasis-associated protein 1 (MTA1) is part of the nucleosome remodelling deacetylation (NuRD) complex involved in global and gene-specific histone deacetylation, alteration of chromatin structure and transcriptional repression [136, 137]. This complex, which also contains Histone DeACetylase (HDAC)1 and HDAC2, plays an essential role in governing deacetylation of histones but also non histone proteins, such as p53 [138]. In addition, green tea polyphenols have been shown to behave as HDAC class I inhibitors which results in p21 and Bax expression irrespective of p53 status in prostate cancer cells [139, 140]. Moreover HDAC inhibition by EGCG is associated with p53 acetylation in p53-wild-type LNCAP prostate cancer cells suggesting an increase of p53 halftime and binding to p21 and Bax promoters as previously described [141]. The mechanism by which HDAC inhibition could induce apoptosis in absence of functional p53 in p53-null PC3 prostate cancer cells might be related to interaction with p73 pathway as previously suggested [142, 143] or direct regulation of p21 promoter activation [144]. Similar HDAC inhibition by curcumin has been also seen in prostate cancer cells [145]. However the exact role of HDAC inhibition in polyphenol-induced apoptosis of cancer cells remains to be elucidated especially in vivo.

7. Role of oxidative stress and DNA damage in p53/p73 regulation by polyphenols

Polyphenolic compounds have been extensively described as anti-oxidant molecules with the capability to scavenge reactive oxygen species (ROS), which include radical oxygen and nitrogen species such as O2- (superoxide anion), HO. (hydroxyl radical), NO. (nitric oxide radical), ONOO-. (peroxinitrite anion) and H2O2 (hydrogen peroxide), as well as oxidatively generated free radicals RO. and ROO. from biomolecules like lipids, proteins or nucleic acids (DNA and RNA) [3, 146]. Polyphenols are not only able to quench the ROS but also to regulate directly the oxidative stress-mediated enzyme activity, therefore reducing the formation of ROS. These anti-oxidant properties have been linked to the polyphenol-mediated reduction of chronic disease risk including cancer chemoprevention [13, 147]. Indeed, redox changes are often reported as important inducer of neoplastic transformation as well as chemoresistance. Cerutti et al. identified for the first time in 1985 the close relationship between pro-oxidant conditions and cancer development [148]. More than twenty years later, accumulated evidences indicate that the non-physiological alterations of the intracellular redox state could be considered as a hallmark of tumor biology. Indeed, redox changes have been involved in several key events of carcinogenesis such as self-sufficiency in growth signals [149, 150], resistance to apoptosis [151, 152], sustained angiogenesis [153, 154], autophagy and invasiveness. However, recent findings also suggest that this redox changes might be exploited as therapeutic strategy to selectively kill tumor cells.

Recently and unexpectedly, it has been established that various and structurally different (flavonoids or non-flavonoids) polyphenols are able to induce ROS (mainly superoxide anions or hydrogen peroxide) formation in cancer cells and for some of them to activate the DNA-damage response pathway [51, 79, 80, 95, 102, 103, 155-158]. Heiss et al. have also shown that the resveratrol-induced senescence in colon cancer cells is dependent upon an increased formation of ROS and the subsequent phosphorylation of p53 on the Ser15, suggesting a relationship between polyphenol-induced oxidative stress and p53 activation [103]. On the other hand, curcumin and wogonin induce ROS production and cause cytotoxicity in p53+/+ and p53-/- cancer cells [56, 64], indicating that ROS formation is an event independent of p53 and might be an earlier step in the cell death pathway. This hypothesis is supported by the study showing ROS in cancer cells as earlier as 20 minutes after the beginning of wogonin treatment. Moreover, in the same study, the subsequent up-regulation of p53 (maximal activation at 16 hours) is significantly inhibited by anti-oxidants such as N-Acetyl-Cysteine. Importantly, most of the studies did not investigate the possible alternative role of p73 in p53-mutated cells, but we and others have shown that in p53-mutated or p53-deficient cells, a polyphenolic compound (EGCG) or source (red wine polyphenolic extract, polyphenol-rich aronia juice) strongly induced oxidative stress-mediated up-regulation of p73 and apoptosis [79, 80, 84]. Further reports also supported that p53-family tumor suppressors regulation might be related to oxidative stress [159].

Interestingly, the cytotoxic effects induced by curcumin or its analogue HO-3867 were reduced in non-cancerous cells as well as the ROS formation in comparison to human ovarian cancer cells. This suggests that the specific pro-oxidant activity of polyphenols in cancer cells might explain the selective anticancer properties of these compounds, sparing healthy normal cells [107, 160]. Similarly, EGCG increased preferentially ROS formation, p53 and p21 expression and cytotoxicity in colorectal cancer cells but not in human embryonic kidney cells and normal human lung cell line [157].

Oxidative stress is one of the major conditions that damages DNA, acting as a mediator of environmental stressors such as UV- and X-rays irradiation, drugs, and of metabolic imbalance [161]. Since p53 might be regulated by the redox environment [162], especially by the ROS/DNA damage pathway, it has been proposed that polyphenol-mediated anticancer effects are related to a ROS/DNA damage/p53 pathway (Figure 1). Indeed polyphenol-induced DNA damage and apoptosis have been demonstrated with various compounds such as curcumin in glioblastoma and prostate cancer cells [100, 163], resveratrol in prostate cancer cells [164, 165], EGCG in lung cancer cells and xenograft in mice [166], wogonin in glioblastoma and prostate cancer cells [51, 56], and luteolin in lung and head and neck cancer cells [58]. Therefore the current molecular mechanism of the anticancer properties of polyphenols might involve selective ROS formation together with DNA damage in cancer cells. Thus, this process might lead to the regulation of several pathways (ATM/DNA-PK, MAPKs, p300, SIRT1, HDAC, see Figure 1), and ultimately to the expression and stabilization of p53-family tumor suppressors triggering programmed cell death.

8. Therapeutic perspectives

Recent investigations have demonstrated additional or synergistic effects when polyphenols are combined with chemo- or radiotherapy. Indeed, resveratrol induces synergistic apoptosis with 5-fluorouracile [167]. Similar observations have been made with curcumin associated with doxorubicin, cisplatin, gemcitabine or radiation for cell death induction of glioblastoma cells and prostate cancer cells [60, 87]. More importantly, curcumin and its analogue, HO-3867 sensitized doxorubicin-resistant ascite carcinoma cells and breast cancer cells as well as cisplatin-resistant ovarian carcinoma cells together with enhanced p53 expression [107, 120, 168, 169]. Similarly, EGCG displayed synergistic upregulation of p53 and p73 as well as anticancer properties with taxanes (paclitaxel and docetaxel) in vitro but also in vivo in prostate cancer models [170, 171]. Because all of the previously mentioned drugs demonstrated the ability to induce DNA damage, it is likely that polyphenols might amplify these damages leading therefore to synergistic effects. Surprisingly, EGCG has also synergistic effects with targeted therapy such as erlotinib (inhibitor of epidermal growth factor receptor) to induce p53 phosphorylation on Ser15 and expression together with apoptosis [172].

Interestingly, curcumin also ameliorated oxaliplatin-induced chemoresistance in colorectal cancer cells without significant effect on p53 expression [173]. Similarly, curcumin and EGCG sensitized glioma cells in vitro and in vivo to chemotherapeutic drugs and also to radiation in a p53-independent manner [163]. These data suggest that polyphenols can effectively circumvent resistance of cancer cells to chemotherapy, but likely through a p53-independent pathway.

Numerous in vitro studies have demonstrated the cytotoxic effects of polyphenols by using micromolar concentrations which are much higher than current chemotherapeutic drugs under development. However, polyphenols still keep their potential as chemotherapeutic drug, firstly because of their activity on chemo- or radioresistant cancer cells and secondly because of their very low toxicity on healthy tissues giving them a large therapeutic index. Indeed, many recent in vitro studies have highlighted the selective pro-apoptotic properties of polyphenols or analogues with no or low cytotoxic effect on non-cancer healthy cells, such as endothelial cells, cardiomyocytes, lymphocytes, chondrocytes, ovarian cells, prostate and mammary epithelial cells, astrocytes, or neurons [54, 57, 60, 79, 95, 107, 158, 163, 169, 174]. Interestingly, the selective pro-apoptotic effect of curcumin in breast cancer cells is associated with an increased expression of p53, whereas p53 is only slightly upregulated in normal mammary epithelial cells, suggesting a selective activation of p53 pathway in cancer cells sparing normal cells [54]. Moreover, in vivo treatment with polyphenolic compounds or products in tumor model such as cancer cells xenografts induced a significant inhibition of tumor growth together with a very good tolerance for healthy tissues, including heart, liver, kidney, lung and haematopoietic tissue [60, 78]. However, more animal studies and human clinical trials are now necessary to clearly determine whether polyphenols or their natural nutritional sources are safe and efficient to treat cancer.

9. Concluding remarks

The present literature review has summarized the results of recent studies focusing mainly on the p53-related anticancer properties of three major polyphenolic compounds (resveratrol, curcumin and EGCG). Despite highly active research in this area, the data are still controversial concerning the possible key role of the tumor suppressor p53 in the polyphenol-mediated apoptosis of tumor cells. However, according to the emerging evidences suggesting that polyphenols might alternatively regulate also the structurally- and functionally-related tumor suppressors such as p73, these natural compounds might be considered as general executors of the p53 family-mediated programmed cell death in cancer cells. Importantly, the selective anticancer properties of polyphenols are maintained even when p53 is mutated or absent, as well as when cells are resistant to current therapies. However, further investigations are still mandatory to better understand the underlying molecular mechanism in vitro as well as in vivo before a potential clinical development.


1 - Es-Safi N. Plant Polyphenols: Extraction, Structural Characterization, Hemisynthesis and Antioxidant Properties. In: Rao DV, editor. Phytochemicals as Nutraceuticals - Global Approaches to Their Role in Nutrition and Health: INTECH; 2012. p. 181-206.
2 - Cheynier V. Polyphenols in foods are more complex than often thought. The American journal of clinical nutrition. 2005;81(1 Suppl):223S-9S.
3 - Quideau S, Deffieux D, Douat-Casassus C, Pouysegu L. Plant polyphenols: chemical properties, biological activities, and synthesis. Angewandte Chemie. 2011;50(3):586-621.
4 - Neveu V, Perez-Jimenez J, Vos F, Crespy V, du Chaffaut L, Mennen L, et al. Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database (Oxford). 2010;doi: 10.1093/database/bap024. (accessed 10 January 2013).
5 - Kris-Etherton PM, Hecker KD, Bonanome A, Coval SM, Binkoski AE, Hilpert KF, et al. Bioactive compounds in foods: their role in the prevention of cardiovascular disease and cancer. The American journal of medicine. 2002;113 Suppl 9B:71S-88S.
6 - Andriantsitohaina R, Auger C, Chataigneau T, Etienne-Selloum N, Li H, Martinez MC, et al. Molecular mechanisms of the cardiovascular protective effects of polyphenols. The British journal of nutrition. 2012:1-18.
7 - Schini-Kerth VB, Etienne-Selloum N, Chataigneau T, Auger C. Vascular protection by natural product-derived polyphenols: in vitro and in vivo evidence. Planta medica. 2011;77(11):1161-7.
8 - Di Castelnuovo A, di Giuseppe R, Iacoviello L, de Gaetano G. Consumption of cocoa, tea and coffee and risk of cardiovascular disease. European journal of internal medicine. 2012;23(1):15-25.
9 - Dauchet L, Amouyel P, Hercberg S, Dallongeville J. Fruit and vegetable consumption and risk of coronary heart disease: a meta-analysis of cohort studies. The Journal of nutrition. 2006;136(10):2588-93.
10 - Sofi F, Abbate R, Gensini GF, Casini A. Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis. The American journal of clinical nutrition. 2010;92(5):1189-96.
11 - Aune D, Lau R, Chan DS, Vieira R, Greenwood DC, Kampman E, et al. Nonlinear reduction in risk for colorectal cancer by fruit and vegetable intake based on meta-analysis of prospective studies. Gastroenterology. 2011;141(1):106-18.
12 - Riboli E, Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk. The American journal of clinical nutrition. 2003;78(3 Suppl):559S-69S.
13 - Ramos S. Cancer chemoprevention and chemotherapy: dietary polyphenols and signalling pathways. Molecular nutrition & food research. 2008;52(5):507-26.
14 - Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nature reviews Cancer. 2003;3(10):768-80.
15 - Dai Q, Borenstein AR, Wu Y, Jackson JC, Larson EB. Fruit and vegetable juices and Alzheimer's disease: the Kame Project. The American journal of medicine. 2006;119(9):751-9.
16 - Bastianetto S, Krantic S, Chabot JG, Quirion R. Possible involvement of programmed cell death pathways in the neuroprotective action of polyphenols. Current Alzheimer research. 2011;8(5):445-51.
17 - Villegas I, Sanchez-Fidalgo S, de la Lastra CA. Chemopreventive effect of dietary curcumin on inflammation-induced colorectal carcinogenesis in mice. Molecular nutrition & food research. 2011;55(2):259-67.
18 - Roy P, Kalra N, Prasad S, George J, Shukla Y. Chemopreventive potential of resveratrol in mouse skin tumors through regulation of mitochondrial and PI3K/AKT signaling pathways. Pharm Res. 2009;26(1):211-7.
19 - Yang CS, Wang H. Mechanistic issues concerning cancer prevention by tea catechins. Molecular nutrition & food research. 2011;55(6):819-31.
20 - Linzer DI, Levine AJ. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. Cell. 1979;17(1):43-52.
21 - DeLeo AB, Jay G, Appella E, Dubois GC, Law LW, Old LJ. Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proceedings of the National Academy of Sciences of the United States of America. 1979;76(5):2420-4.
22 - Lane DP, Crawford LV. T antigen is bound to a host protein in SV40-transformed cells. Nature. 1979;278(5701):261-3.
23 - Laptenko O, Prives C. Transcriptional regulation by p53: one protein, many possibilities. Cell death and differentiation. 2006;13(6):951-61.
24 - Speidel D. Transcription-independent p53 apoptosis: an alternative route to death. Trends Cell Biol. 2010;20(1):14-24.
25 - Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358(6381):15-6.
26 - Horn HF, Vousden KH. Coping with stress: multiple ways to activate p53. Oncogene. 2007;26(9):1306-16.
27 - Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387(6630):296-9.
28 - Soussi T, Wiman KG. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer cell. 2007;12(4):303-12.
29 - Edlund K, Larsson O, Ameur A, Bunikis I, Gyllensten U, Leroy B, et al. Data-driven unbiased curation of the TP53 tumor suppressor gene mutation database and validation by ultradeep sequencing of human tumors. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(24):9551-6.
30 - Soussi T, Ishioka C, Claustres M, Beroud C. Locus-specific mutation databases: pitfalls and good practice based on the p53 experience. Nature reviews Cancer. 2006;6(1):83-90.
31 - Zhang XP, Liu F, Wang W. Coordination between cell cycle progression and cell fate decision by the p53 and E2F1 pathways in response to DNA damage. The Journal of biological chemistry. 2010;285(41):31571-80.
32 - Avery-Kiejda KA, Bowden NA, Croft AJ, Scurr LL, Kairupan CF, Ashton KA, et al. P53 in human melanoma fails to regulate target genes associated with apoptosis and the cell cycle and may contribute to proliferation. BMC cancer. 2011;11:203.
33 - Kuribayashi K, El-Deiry WS. Regulation of programmed cell death by the p53 pathway. Advances in experimental medicine and biology. 2008;615:201-21.
34 - Brooks CL, Gu W. p53 ubiquitination: Mdm2 and beyond. Molecular cell. 2006;21(3):307-15.
35 - Wade M, Wahl GM. Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol Cancer Res. 2009;7(1):1-11.
36 - Kaghad M, Bonnet H, Yang A, Creancier L, Biscan JC, Valent A, et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell. 1997;90(4):809-19.
37 - Trink B, Okami K, Wu L, Sriuranpong V, Jen J, Sidransky D. A new human p53 homologue. Nat Med. 1998;4(7):747-8.
38 - Collavin L, Lunardi A, Del Sal G. p53-family proteins and their regulators: hubs and spokes in tumor suppression. Cell death and differentiation. 2010;17(6):901-11.
39 - Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A. p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature. 1999;398(6729):708-13.
40 - Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature. 2000;404(6773):99-103.
41 - Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CA, Jr., Butel JS, et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356(6366):215-21.
42 - Guo X, Keyes WM, Papazoglu C, Zuber J, Li W, Lowe SW, et al. TAp63 induces senescence and suppresses tumorigenesis in vivo. Nature cell biology. 2009;11(12):1451-7.
43 - Grande L, Bretones G, Rosa-Garrido M, Garrido-Martin EM, Hernandez T, Fraile S, et al. Transcription factors Sp1 and p73 control the expression of the proapoptotic protein NOXA in the response of testicular embryonal carcinoma cells to cisplatin. The Journal of biological chemistry. 2012;287(32):26495-505.
44 - Leong CO, Vidnovic N, DeYoung MP, Sgroi D, Ellisen LW. The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J Clin Invest. 2007;117(5):1370-80.
45 - Lin YL, Sengupta S, Gurdziel K, Bell GW, Jacks T, Flores ER. p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS genetics. 2009;5(10):e1000680.
46 - Deyoung MP, Ellisen LW. p63 and p73 in human cancer: defining the network. Oncogene. 2007;26(36):5169-83.
47 - Zaika AI, Slade N, Erster SH, Sansome C, Joseph TW, Pearl M, et al. DeltaNp73, a dominant-negative inhibitor of wild-type p53 and TAp73, is up-regulated in human tumors. J Exp Med. 2002;196(6):765-80.
48 - Tanigawa S, Fujii M, Hou DX. Stabilization of p53 is involved in quercetin-induced cell cycle arrest and apoptosis in HepG2 cells. Bioscience, biotechnology, and biochemistry. 2008;72(3):797-804.
49 - Shi R, Huang Q, Zhu X, Ong YB, Zhao B, Lu J, et al. Luteolin sensitizes the anticancer effect of cisplatin via c-Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization. Molecular cancer therapeutics. 2007;6(4):1338-47.
50 - Sakamoto T, Horiguchi H, Oguma E, Kayama F. Effects of diverse dietary phytoestrogens on cell growth, cell cycle and apoptosis in estrogen-receptor-positive breast cancer cells. J Nutr Biochem. 2010;21(9):856-64.
51 - Lee DH, Lee TH, Jung CH, Kim YH. Wogonin induces apoptosis by activating the AMPK and p53 signaling pathways in human glioblastoma cells. Cell Signal. 2012;24(11):2216-25.
52 - Basile V, Ferrari E, Lazzari S, Belluti S, Pignedoli F, Imbriano C. Curcumin derivatives: molecular basis of their anti-cancer activity. Biochemical pharmacology. 2009;78(10):1305-15.
53 - Hastak K, Agarwal MK, Mukhtar H, Agarwal ML. Ablation of either p21 or Bax prevents p53-dependent apoptosis induced by green tea polyphenol epigallocatechin-3-gallate. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2005;19(7):789-91.
54 - Choudhuri T, Pal S, Das T, Sa G. Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner. The Journal of biological chemistry. 2005;280(20):20059-68.
55 - Thakur VS, Ruhul Amin AR, Paul RK, Gupta K, Hastak K, Agarwal MK, et al. p53-Dependent p21-mediated growth arrest pre-empts and protects HCT116 cells from PUMA-mediated apoptosis induced by EGCG. Cancer letters. 2010;296(2):225-32.
56 - Lee DH, Rhee JG, Lee YJ. Reactive oxygen species up-regulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin. British journal of pharmacology. 2009;157(7):1189-202.
57 - Lee HP, Li TM, Tsao JY, Fong YC, Tang CH. Curcumin induces cell apoptosis in human chondrosarcoma through extrinsic death receptor pathway. International immunopharmacology. 2012;13(2):163-9.
58 - Amin AR, Wang D, Zhang H, Peng S, Shin HJ, Brandes JC, et al. Enhanced anti-tumor activity by the combination of the natural compounds (-)-epigallocatechin-3-gallate and luteolin: potential role of p53. The Journal of biological chemistry. 2010;285(45):34557-65.
59 - Hossain MM, Banik NL, Ray SK. Synergistic anti-cancer mechanisms of curcumin and paclitaxel for growth inhibition of human brain tumor stem cells and LN18 and U138MG cells. Neurochem Int. 2012;61(7):1102-13.
60 - Zanotto-Filho A, Braganhol E, Edelweiss MI, Behr GA, Zanin R, Schroder R, et al. The curry spice curcumin selectively inhibits cancer cells growth in vitro and in preclinical model of glioblastoma. J Nutr Biochem. 2012;23(6):591-601.
61 - Nautiyal J, Kanwar SS, Yu Y, Majumdar AP. Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal. 2011;6:7.
62 - Chan JY, Phoo MS, Clement MV, Pervaiz S, Lee SC. Resveratrol displays converse dose-related effects on 5-fluorouracil-evoked colon cancer cell apoptosis: the roles of caspase-6 and p53. Cancer Biol Ther. 2008;7(8):1305-12.
63 - Majumdar AP, Banerjee S, Nautiyal J, Patel BB, Patel V, Du J, et al. Curcumin synergizes with resveratrol to inhibit colon cancer. Nutr Cancer. 2009;61(4):544-53.
64 - Watson JL, Hill R, Yaffe PB, Greenshields A, Walsh M, Lee PW, et al. Curcumin causes superoxide anion production and p53-independent apoptosis in human colon cancer cells. Cancer letters. 2010;297(1):1-8.
65 - Sukumari-Ramesh S, Bentley JN, Laird MD, Singh N, Vender JR, Dhandapani KM. Dietary phytochemicals induce p53- and caspase-independent cell death in human neuroblastoma cells. Int J Dev Neurosci. 2011;29(7):701-10.
66 - Gupta K, Thakur VS, Bhaskaran N, Nawab A, Babcook MA, Jackson MW, et al. Green Tea Polyphenols Induce p53-Dependent and p53-Independent Apoptosis in Prostate Cancer Cells through Two Distinct Mechanisms. PloS one. 2012;7(12):e52572.
67 - Onoda C, Kuribayashi K, Nirasawa S, Tsuji N, Tanaka M, Kobayashi D, et al. (-)-Epigallocatechin-3-gallate induces apoptosis in gastric cancer cell lines by down-regulating survivin expression. International journal of oncology. 2011;38(5):1403-8.
68 - Chiu TL, Su CC. Curcumin inhibits proliferation and migration by increasing the Bax to Bcl-2 ratio and decreasing NF-kappaBp65 expression in breast cancer MDA-MB-231 cells. International journal of molecular medicine. 2009;23(4):469-75.
69 - Ferraz da Costa DC, Casanova FA, Quarti J, Malheiros MS, Sanches D, Dos Santos PS, et al. Transient Transfection of a Wild-Type p53 Gene Triggers Resveratrol-Induced Apoptosis in Cancer Cells. PloS one. 2012;7(11):e48746.
70 - Thiel G, Cibelli G. Regulation of life and death by the zinc finger transcription factor Egr-1. Journal of cellular physiology. 2002;193(3):287-92.
71 - Choi BH, Kim CG, Bae YS, Lim Y, Lee YH, Shin SY. p21 Waf1/Cip1 expression by curcumin in U-87MG human glioma cells: role of early growth response-1 expression. Cancer research. 2008;68(5):1369-77.
72 - Whitlock NC, Bahn JH, Lee SH, Eling TE, Baek SJ. Resveratrol-induced apoptosis is mediated by early growth response-1, Kruppel-like factor 4, and activating transcription factor 3. Cancer Prev Res (Phila). 2011;4(1):116-27.
73 - Moon Y, Lee M, Yang H. Involvement of early growth response gene 1 in the modulation of microsomal prostaglandin E synthase 1 by epigallocatechin gallate in A549 human pulmonary epithelial cells. Biochemical pharmacology. 2007;73(1):125-35.
74 - Zhang Q, Zhao XH, Wang ZJ. Cytotoxicity of flavones and flavonols to a human esophageal squamous cell carcinoma cell line (KYSE-510) by induction of G2/M arrest and apoptosis. Toxicol In Vitro. 2009;23(5):797-807.
75 - Shammas MA, Neri P, Koley H, Batchu RB, Bertheau RC, Munshi V, et al. Specific killing of multiple myeloma cells by (-)-epigallocatechin-3-gallate extracted from green tea: biologic activity and therapeutic implications. Blood. 2006;108(8):2804-10.
76 - Achour M, Mousli M, Alhosin M, Ibrahim A, Peluso J, Muller CD, et al. Epigallocatechin-3-gallate up-regulates tumor suppressor gene expression via a reactive oxygen species-dependent down-regulation of UHRF1. Biochem Biophys Res Commun. 2013;430(1):208-12.
77 - Thangasamy T, Sittadjody S, Mitchell GC, Mendoza EE, Radhakrishnan VM, Limesand KH, et al. Quercetin abrogates chemoresistance in melanoma cells by modulating deltaNp73. BMC cancer. 2010;10:282.
78 - Walter A, Etienne-Selloum N, Brasse D, Khallouf H, Bronner C, Rio MC, et al. Intake of grape-derived polyphenols reduces C26 tumor growth by inhibiting angiogenesis and inducing apoptosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2010;24(9):3360-9.
79 - Sharif T, Alhosin M, Auger C, Minker C, Kim JH, Etienne-Selloum N, et al. Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3-dependent apoptosis in human leukemia cells. PloS one. 2012;7(3):e32526.
80 - Sharif T, Auger C, Alhosin M, Ebel C, Achour M, Etienne-Selloum N, et al. Red wine polyphenols cause growth inhibition and apoptosis in acute lymphoblastic leukaemia cells by inducing a redox-sensitive up-regulation of p73 and down-regulation of UHRF1. Eur J Cancer. 2010;46(5):983-94.
81 - Somasagara RR, Hegde M, Chiruvella KK, Musini A, Choudhary B, Raghavan SC. Extracts of strawberry fruits induce intrinsic pathway of apoptosis in breast cancer cells and inhibits tumor progression in mice. PloS one. 2012;7(10):e47021.
82 - Azmi AS, Ali S, Banerjee S, Bao B, Maitah MN, Padhye S, et al. Network modeling of CDF treated pancreatic cancer cells reveals a novel c-myc-p73 dependent apoptotic mechanism. Am J Transl Res. 2011;3(4):374-82.
83 - Singh M, Singh N. Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells. Mol Cell Biochem. 2011;347(1-2):1-11.
84 - Amin AR, Thakur VS, Paul RK, Feng GS, Qu CK, Mukhtar H, et al. SHP-2 tyrosine phosphatase inhibits p73-dependent apoptosis and expression of a subset of p53 target genes induced by EGCG. Proceedings of the National Academy of Sciences of the United States of America. 2007;104(13):5419-24.
85 - Zhang Z, Wang H, Li M, Agrawal S, Chen X, Zhang R. MDM2 is a negative regulator of p21WAF1/CIP1, independent of p53. The Journal of biological chemistry. 2004;279(16):16000-6.
86 - Shangary S, Wang S. Targeting the MDM2-p53 interaction for cancer therapy. Clin Cancer Res. 2008;14(17):5318-24.
87 - Li M, Zhang Z, Hill DL, Wang H, Zhang R. Curcumin, a dietary component, has anticancer, chemosensitization, and radiosensitization effects by down-regulating the MDM2 oncogene through the PI3K/mTOR/ETS2 pathway. Cancer research. 2007;67(5):1988-96.
88 - Liu H, Liang Y, Wang L, Tian L, Song R, Han T, et al. In Vivo and In Vitro Suppression of Hepatocellular Carcinoma by EF24, a Curcumin Analog. PloS one. 2012;7(10):e48075.
89 - Hastak K, Gupta S, Ahmad N, Agarwal MK, Agarwal ML, Mukhtar H. Role of p53 and NF-kappaB in epigallocatechin-3-gallate-induced apoptosis of LNCaP cells. Oncogene. 2003;22(31):4851-9.
90 - Manna S, Banerjee S, Mukherjee S, Das S, Panda CK. Epigallocatechin gallate induced apoptosis in Sarcoma180 cells in vivo: mediated by p53 pathway and inhibition in U1B, U4-U6 UsnRNAs expression. Apoptosis. 2006;11(12):2267-76.
91 - Dai JM, Wang ZY, Sun DC, Lin RX, Wang SQ. SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. Journal of cellular physiology. 2007;210(1):161-6.
92 - Young LF, Hantz HL, Martin KR. Resveratrol modulates gene expression associated with apoptosis, proliferation and cell cycle in cells with mutated human c-Ha-Ras, but does not alter c-Ha-Ras mRNA or protein expression. J Nutr Biochem. 2005;16(11):663-74.
93 - Moll UM, Zaika A. Nuclear and mitochondrial apoptotic pathways of p53. FEBS Lett. 2001;493(2-3):65-9.
94 - Liontas A, Yeger H. Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma. Anticancer research. 2004;24(2B):987-98.
95 - Shankar S, Srivastava RK. Involvement of Bcl-2 family members, phosphatidylinositol 3'-kinase/AKT and mitochondrial p53 in curcumin (diferulolylmethane)-induced apoptosis in prostate cancer. International journal of oncology. 2007;30(4):905-18.
96 - Dai C, Gu W. p53 post-translational modification: deregulated in tumorigenesis. Trends Mol Med. 2010;16(11):528-36.
97 - Olsson A, Manzl C, Strasser A, Villunger A. How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression? Cell death and differentiation. 2007;14(9):1561-75.
98 - Bartek J, Bartkova J, Lukas J. DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene. 2007;26(56):7773-9.
99 - Aziz K, Nowsheen S, Pantelias G, Iliakis G, Gorgoulis VG, Georgakilas AG. Targeting DNA damage and repair: embracing the pharmacological era for successful cancer therapy. Pharmacology & therapeutics. 2012;133(3):334-50.
100 - Ide H, Yu J, Lu Y, China T, Kumamoto T, Koseki T, et al. Testosterone augments polyphenol-induced DNA damage response in prostate cancer cell line, LNCaP. Cancer science. 2011;102(2):468-71.
101 - Kang SU, Lee BS, Lee SH, Baek SJ, Shin YS, Kim CH. Expression of NSAID-activated gene-1 by EGCG in head and neck cancer: involvement of ATM-dependent p53 expression. J Nutr Biochem. 2012.
102 - Ye R, Goodarzi AA, Kurz EU, Saito S, Higashimoto Y, Lavin MF, et al. The isoflavonoids genistein and quercetin activate different stress signaling pathways as shown by analysis of site-specific phosphorylation of ATM, p53 and histone H2AX. DNA repair. 2004;3(3):235-44.
103 - Heiss EH, Schilder YD, Dirsch VM. Chronic treatment with resveratrol induces redox stress- and ataxia telangiectasia-mutated (ATM)-dependent senescence in p53-positive cancer cells. The Journal of biological chemistry. 2007;282(37):26759-66.
104 - Heo JI, Oh SJ, Kho YJ, Kim JH, Kang HJ, Park SH, et al. ATM mediates interdependent activation of p53 and ERK through formation of a ternary complex with p-p53 and p-ERK in response to DNA damage. Mol Biol Rep. 2012;39(8):8007-14.
105 - She QB, Chen N, Dong Z. ERKs and p38 kinase phosphorylate p53 protein at serine 15 in response to UV radiation. The Journal of biological chemistry. 2000;275(27):20444-9.
106 - Watson JL, Greenshields A, Hill R, Hilchie A, Lee PW, Giacomantonio CA, et al. Curcumin-induced apoptosis in ovarian carcinoma cells is p53-independent and involves p38 mitogen-activated protein kinase activation and downregulation of Bcl-2 and survivin expression and Akt signaling. Mol Carcinog. 2010;49(1):13-24.
107 - Weir NM, Selvendiran K, Kutala VK, Tong L, Vishwanath S, Rajaram M, et al. Curcumin induces G2/M arrest and apoptosis in cisplatin-resistant human ovarian cancer cells by modulating Akt and p38 MAPK. Cancer Biol Ther. 2007;6(2):178-84.
108 - She QB, Bode AM, Ma WY, Chen NY, Dong Z. Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase. Cancer research. 2001;61(4):1604-10.
109 - Lin HY, Sun M, Tang HY, Simone TM, Wu YH, Grandis JR, et al. Resveratrol causes COX-2- and p53-dependent apoptosis in head and neck squamous cell cancer cells. J Cell Biochem. 2008;104(6):2131-42.
110 - Lin C, Crawford DR, Lin S, Hwang J, Sebuyira A, Meng R, et al. Inducible COX-2-dependent apoptosis in human ovarian cancer cells. Carcinogenesis. 2011;32(1):19-26.
111 - Conforti F, Sayan AE, Sreekumar R, Sayan BS. Regulation of p73 activity by post-translational modifications. Cell Death Dis. 2012;3:e285.
112 - Luo J, Su F, Chen D, Shiloh A, Gu W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature. 2000;408(6810):377-81.
113 - Goodman RH, Smolik S. CBP/p300 in cell growth, transformation, and development. Genes Dev. 2000;14(13):1553-77.
114 - Iyer NG, Ozdag H, Caldas C. p300/CBP and cancer. Oncogene. 2004;23(24):4225-31.
115 - Barlev NA, Liu L, Chehab NH, Mansfield K, Harris KG, Halazonetis TD, et al. Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases. Molecular cell. 2001;8(6):1243-54.
116 - Iyer NG, Chin SF, Ozdag H, Daigo Y, Hu DE, Cariati M, et al. p300 regulates p53-dependent apoptosis after DNA damage in colorectal cancer cells by modulation of PUMA/p21 levels. Proceedings of the National Academy of Sciences of the United States of America. 2004;101(19):7386-91.
117 - Costanzo A, Merlo P, Pediconi N, Fulco M, Sartorelli V, Cole PA, et al. DNA damage-dependent acetylation of p73 dictates the selective activation of apoptotic target genes. Molecular cell. 2002;9(1):175-86.
118 - Narayanan BA, Narayanan NK, Re GG, Nixon DW. Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. International journal of cancer Journal international du cancer. 2003;104(2):204-12.
119 - Tang HY, Shih A, Cao HJ, Davis FB, Davis PJ, Lin HY. Resveratrol-induced cyclooxygenase-2 facilitates p53-dependent apoptosis in human breast cancer cells. Molecular cancer therapeutics. 2006;5(8):2034-42.
120 - Sen GS, Mohanty S, Hossain DM, Bhattacharyya S, Banerjee S, Chakraborty J, et al. Curcumin enhances the efficacy of chemotherapy by tailoring p65NFkappaB-p300 cross-talk in favor of p53-p300 in breast cancer. The Journal of biological chemistry. 2011;286(49):42232-47.
121 - Brooks CL, Gu W. How does SIRT1 affect metabolism, senescence and cancer? Nature reviews Cancer. 2009;9(2):123-8.
122 - Stunkel W, Campbell RM. Sirtuin 1 (SIRT1): the misunderstood HDAC. Journal of biomolecular screening. 2011;16(10):1153-69.
123 - Herranz D, Serrano M. SIRT1: recent lessons from mouse models. Nature reviews Cancer. 2010;10(12):819-23.
124 - Saunders LR, Verdin E. Sirtuins: critical regulators at the crossroads between cancer and aging. Oncogene. 2007;26(37):5489-504.
125 - Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001;107(2):149-59.
126 - Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001;107(2):137-48.
127 - Ikenoue T, Inoki K, Zhao B, Guan KL. PTEN acetylation modulates its interaction with PDZ domain. Cancer research. 2008;68(17):6908-12.
128 - Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N, et al. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS genetics. 2011;7(6):e1002135.
129 - Frazzi R, Valli R, Tamagnini I, Casali B, Latruffe N, Merli F. Resveratrol-mediated apoptosis of hodgkin lymphoma cells involves SIRT1 inhibition and FOXO3a hyperacetylation. International journal of cancer Journal international du cancer. 2012.
130 - Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003;425(6954):191-6.
131 - Baur JA, Ungvari Z, Minor RK, Le Couteur DG, de Cabo R. Are sirtuins viable targets for improving healthspan and lifespan? Nature reviews Drug discovery. 2012;11(6):443-61.
132 - Pizarro JG, Verdaguer E, Ancrenaz V, Junyent F, Sureda F, Pallas M, et al. Resveratrol inhibits proliferation and promotes apoptosis of neuroblastoma cells: role of sirtuin 1. Neurochemical research. 2011;36(2):187-94.
133 - Singh NP, Singh UP, Hegde VL, Guan H, Hofseth L, Nagarkatti M, et al. Resveratrol (trans-3,5,4'-trihydroxystilbene) suppresses EL4 tumor growth by induction of apoptosis involving reciprocal regulation of SIRT1 and NF-kappaB. Molecular nutrition & food research. 2011;55(8):1207-18.
134 - Han DW, Lee MH, Kim B, Lee JJ, Hyon SH, Park JC. Preventive Effects of Epigallocatechin-3-O-Gallate against Replicative Senescence Associated with p53 Acetylation in Human Dermal Fibroblasts. Oxid Med Cell Longev. 2012;2012:850684.
135 - Kai L, Samuel SK, Levenson AS. Resveratrol enhances p53 acetylation and apoptosis in prostate cancer by inhibiting MTA1/NuRD complex. International journal of cancer Journal international du cancer. 2010;126(7):1538-48.
136 - Toh Y, Pencil SD, Nicolson GL. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metastatic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. The Journal of biological chemistry. 1994;269(37):22958-63.
137 - Xue Y, Wong J, Moreno GT, Young MK, Cote J, Wang W. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Molecular cell. 1998;2(6):851-61.
138 - Moon HE, Cheon H, Lee MS. Metastasis-associated protein 1 inhibits p53-induced apoptosis. Oncology reports. 2007;18(5):1311-4.
139 - Thakur VS, Gupta K, Gupta S. Green tea polyphenols increase p53 transcriptional activity and acetylation by suppressing class I histone deacetylases. International journal of oncology. 2012;41(1):353-61.
140 - Thakur VS, Gupta K, Gupta S. Green tea polyphenols causes cell cycle arrest and apoptosis in prostate cancer cells by suppressing class I histone deacetylases. Carcinogenesis. 2012;33(2):377-84.
141 - Mellert HS, Stanek TJ, Sykes SM, Rauscher FJ, 3rd, Schultz DC, McMahon SB. Deacetylation of the DNA-binding domain regulates p53-mediated apoptosis. The Journal of biological chemistry. 2011;286(6):4264-70.
142 - Uramoto H, Wetterskog D, Hackzell A, Matsumoto Y, Funa K. p73 competes with co-activators and recruits histone deacetylase to NF-Y in the repression of PDGF beta-receptor. J Cell Sci. 2004;117(Pt 22):5323-31.
143 - Finzer P, Krueger A, Stohr M, Brenner D, Soto U, Kuntzen C, et al. HDAC inhibitors trigger apoptosis in HPV-positive cells by inducing the E2F-p73 pathway. Oncogene. 2004;23(28):4807-17.
144 - Spiegel S, Milstien S, Grant S. Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy. Oncogene. 2012;31(5):537-51.
145 - Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY, et al. Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. Aaps J. 2011;13(4):606-14.
146 - Perron NR, Brumaghim JL. A review of the antioxidant mechanisms of polyphenol compounds related to iron binding. Cell biochemistry and biophysics. 2009;53(2):75-100.
147 - Kang NJ, Shin SH, Lee HJ, Lee KW. Polyphenols as small molecular inhibitors of signaling cascades in carcinogenesis. Pharmacology & therapeutics. 2011;130(3):310-24.
148 - Cerutti PA. Prooxidant states and tumor promotion. Science. 1985;227(4685):375-81.
149 - Yoo MH, Xu XM, Carlson BA, Patterson AD, Gladyshev VN, Hatfield DL. Targeting thioredoxin reductase 1 reduction in cancer cells inhibits self-sufficient growth and DNA replication. PloS one. 2007;2(10):e1112.
150 - Sun G, Kemble DJ. To C or not to C: direct and indirect redox regulation of Src protein tyrosine kinase. Cell cycle. 2009;8(15):2353-5.
151 - Vaughn AE, Deshmukh M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nature cell biology. 2008;10(12):1477-83.
152 - Salvioli S, Storci G, Pinti M, Quaglino D, Moretti L, Merlo-Pich M, et al. Apoptosis-resistant phenotype in HL-60-derived cells HCW-2 is related to changes in expression of stress-induced proteins that impact on redox status and mitochondrial metabolism. Cell death and differentiation. 2003;10(2):163-74.
153 - Khromova NV, Kopnin PB, Stepanova EV, Agapova LS, Kopnin BP. p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway. Cancer letters. 2009;276(2):143-51.
154 - Kim TH, Hur EG, Kang SJ, Kim JA, Thapa D, Lee YM, et al. NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1alpha. Cancer research. 2011;71(6):2260-75.
155 - Park IJ, Lee YK, Hwang JT, Kwon DY, Ha J, Park OJ. Green tea catechin controls apoptosis in colon cancer cells by attenuation of H2O2-stimulated COX-2 expression via the AMPK signaling pathway at low-dose H2O2. Annals of the New York Academy of Sciences. 2009;1171:538-44.
156 - Su CC, Lin JG, Li TM, Chung JG, Yang JS, Ip SW, et al. Curcumin-induced apoptosis of human colon cancer colo 205 cells through the production of ROS, Ca2+ and the activation of caspase-3. Anticancer research. 2006;26(6B):4379-89.
157 - Min NY, Kim JH, Choi JH, Liang W, Ko YJ, Rhee S, et al. Selective death of cancer cells by preferential induction of reactive oxygen species in response to (-)-epigallocatechin-3-gallate. Biochem Biophys Res Commun. 2012;421(1):91-7.
158 - Shankar S, Chen Q, Siddiqui I, Sarva K, Srivastava RK. Sensitization of TRAIL-resistant LNCaP cells by resveratrol (3, 4', 5 tri-hydroxystilbene): molecular mechanisms and therapeutic potential. J Mol Signal. 2007;2:7.
159 - Maillet A, Pervaiz S. Redox regulation of p53, redox effectors regulated by p53: a subtle balance. Antioxidants & redox signaling. 2012;16(11):1285-94.
160 - Tierney BJ, McCann GA, Cohn DE, Eisenhauer E, Sudhakar M, Kuppusamy P, et al. HO-3867, a STAT3 inhibitor induces apoptosis by inactivation of STAT3 activity in BRCA1-mutated ovarian cancer cells. Cancer Biol Ther. 2012;13(9):766-75.
161 - Kryston TB, Georgiev AB, Pissis P, Georgakilas AG. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res. 2011;711(1-2):193-201.
162 - Meplan C, Richard MJ, Hainaut P. Redox signalling and transition metals in the control of the p53 pathway. Biochemical pharmacology. 2000;59(1):25-33.
163 - Dhandapani KM, Mahesh VB, Brann DW. Curcumin suppresses growth and chemoresistance of human glioblastoma cells via AP-1 and NFkappaB transcription factors. J Neurochem. 2007;102(2):522-38.
164 - Fang Y, DeMarco VG, Nicholl MB. Resveratrol enhances radiation sensitivity in prostate cancer by inhibiting cell proliferation and promoting cell senescence and apoptosis. Cancer science. 2012;103(6):1090-8.
165 - Hsieh TC, Huang YC, Wu JM. Control of prostate cell growth, DNA damage and repair and gene expression by resveratrol analogues, in vitro. Carcinogenesis. 2011;32(1):93-101.
166 - Li GX, Chen YK, Hou Z, Xiao H, Jin H, Lu G, et al. Pro-oxidative activities and dose-response relationship of (-)-epigallocatechin-3-gallate in the inhibition of lung cancer cell growth: a comparative study in vivo and in vitro. Carcinogenesis. 2010;31(5):902-10.
167 - Lee SC, Chan JY, Pervaiz S. Spontaneous and 5-fluorouracil-induced centrosome amplification lowers the threshold to resveratrol-evoked apoptosis in colon cancer cells. Cancer letters. 2010;288(1):36-41.
168 - Selvendiran K, Ahmed S, Dayton A, Kuppusamy ML, Rivera BK, Kalai T, et al. HO-3867, a curcumin analog, sensitizes cisplatin-resistant ovarian carcinoma, leading to therapeutic synergy through STAT3 inhibition. Cancer Biol Ther. 2011;12(9):837-45.
169 - Dayton A, Selvendiran K, Meduru S, Khan M, Kuppusamy ML, Naidu S, et al. Amelioration of doxorubicin-induced cardiotoxicity by an anticancer-antioxidant dual-function compound, HO-3867. J Pharmacol Exp Ther. 2011;339(2):350-7.
170 - Stearns ME, Wang M. Synergistic Effects of the Green Tea Extract Epigallocatechin-3-gallate and Taxane in Eradication of Malignant Human Prostate Tumors. Transl Oncol. 2011;4(3):147-56.
171 - Chen TC, Wang W, Golden EB, Thomas S, Sivakumar W, Hofman FM, et al. Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. Cancer letters. 2011;302(2):100-8.
172 - Amin AR, Khuri FR, Chen ZG, Shin DM. Synergistic growth inhibition of squamous cell carcinoma of the head and neck by erlotinib and epigallocatechin-3-gallate: the role of p53-dependent inhibition of nuclear factor-kappaB. Cancer Prev Res (Phila). 2009;2(6):538-45.
173 - Howells LM, Sale S, Sriramareddy SN, Irving GR, Jones DJ, Ottley CJ, et al. Curcumin ameliorates oxaliplatin-induced chemoresistance in HCT116 colorectal cancer cells in vitro and in vivo. International journal of cancer Journal international du cancer. 2011;129(2):476-86.
174 - Sharif T, Auger C, Bronner C, Alhosin M, Klein T, Etienne-Selloum N, et al. Selective proapoptotic activity of polyphenols from red wine on teratocarcinoma cell, a model of cancer stem-like cell. Invest New Drugs. 2011;29(2):239-47.
175 - Rashid A, Liu C, Sanli T, Tsiani E, Singh G, Bristow RG, et al. Resveratrol enhances prostate cancer cell response to ionizing radiation. Modulation of the AMPK, Akt and mTOR pathways. Radiation oncology. 2011;6:144.
176 - Lin HY, Shih A, Davis FB, Tang HY, Martino LJ, Bennett JA, et al. Resveratrol induced serine phosphorylation of p53 causes apoptosis in a mutant p53 prostate cancer cell line. The Journal of urology. 2002;168(2):748-55.
177 - Hsieh TC, Wong C, John Bennett D, Wu JM. Regulation of p53 and cell proliferation by resveratrol and its derivatives in breast cancer cells: an in silico and biochemical approach targeting integrin alphavbeta3. International journal of cancer Journal international du cancer. 2011;129(11):2732-43.
178 - Singh N, Zaidi D, Shyam H, Sharma R, Balapure AK. Polyphenols sensitization potentiates susceptibility of MCF-7 and MDA MB-231 cells to Centchroman. PloS one. 2012;7(6):e37736.
179 - Lin HY, Lansing L, Merillon JM, Davis FB, Tang HY, Shih A, et al. Integrin alphaVbeta3 contains a receptor site for resveratrol. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2006;20(10):1742-4.
180 - Zhang S, Cao HJ, Davis FB, Tang HY, Davis PJ, Lin HY. Oestrogen inhibits resveratrol-induced post-translational modification of p53 and apoptosis in breast cancer cells. British journal of cancer. 2004;91(1):178-85.
181 - Gogada R, Prabhu V, Amadori M, Scott R, Hashmi S, Chandra D. Resveratrol induces p53-independent, X-linked inhibitor of apoptosis protein (XIAP)-mediated Bax protein oligomerization on mitochondria to initiate cytochrome c release and caspase activation. The Journal of biological chemistry. 2011;286(33):28749-60.
182 - De Amicis F, Giordano F, Vivacqua A, Pellegrino M, Panno ML, Tramontano D, et al. Resveratrol, through NF-Y/p53/Sin3/HDAC1 complex phosphorylation, inhibits estrogen receptor alpha gene expression via p38MAPK/CK2 signaling in human breast cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2011;25(10):3695-707.
183 - Casanova F, Quarti J, da Costa DC, Ramos CA, da Silva JL, Fialho E. Resveratrol chemosensitizes breast cancer cells to melphalan by cell cycle arrest. J Cell Biochem. 2012;113(8):2586-96.
184 - Maccario C, Savio M, Ferraro D, Bianchi L, Pizzala R, Pretali L, et al. The resveratrol analog 4,4'-dihydroxy-trans-stilbene suppresses transformation in normal mouse fibroblasts and inhibits proliferation and invasion of human breast cancer cells. Carcinogenesis. 2012;33(11):2172-80.
185 - Al-Abd AM, Mahmoud AM, El-Sherbiny GA, El-Moselhy MA, Nofal SM, El-Latif HA, et al. Resveratrol enhances the cytotoxic profile of docetaxel and doxorubicin in solid tumour cell lines in vitro. Cell proliferation. 2011;44(6):591-601.
186 - Zhou JH, Cheng HY, Yu ZQ, He DW, Pan Z, Yang DT. Resveratrol induces apoptosis in pancreatic cancer cells. Chinese medical journal. 2011;124(11):1695-9.
187 - Lin H, Xiong W, Zhang X, Liu B, Zhang W, Zhang Y, et al. Notch-1 activation-dependent p53 restoration contributes to resveratrol-induced apoptosis in glioblastoma cells. Oncology reports. 2011;26(4):925-30.
188 - Rusin M, Zajkowicz A, Butkiewicz D. Resveratrol induces senescence-like growth inhibition of U-2 OS cells associated with the instability of telomeric DNA and upregulation of BRCA1. Mechanisms of ageing and development. 2009;130(8):528-37.
189 - Cecchinato V, Chiaramonte R, Nizzardo M, Cristofaro B, Basile A, Sherbet GV, et al. Resveratrol-induced apoptosis in human T-cell acute lymphoblastic leukaemia MOLT-4 cells. Biochemical pharmacology. 2007;74(11):1568-74.
190 - Faber AC, Chiles TC. Resveratrol induces apoptosis in transformed follicular lymphoma OCI-LY8 cells: evidence for a novel mechanism involving inhibition of BCL6 signaling. International journal of oncology. 2006;29(6):1561-6.
191 - George J, Singh M, Srivastava AK, Bhui K, Roy P, Chaturvedi PK, et al. Resveratrol and black tea polyphenol combination synergistically suppress mouse skin tumors growth by inhibition of activated MAPKs and p53. PloS one. 2011;6(8):e23395.
192 - Rajasekaran D, Elavarasan J, Sivalingam M, Ganapathy E, Kumar A, Kalpana K, et al. Resveratrol interferes with N-nitrosodiethylamine-induced hepatocellular carcinoma at early and advanced stages in male Wistar rats. Molecular medicine reports. 2011;4(6):1211-7.
193 - Kalra N, Roy P, Prasad S, Shukla Y. Resveratrol induces apoptosis involving mitochondrial pathways in mouse skin tumorigenesis. Life sciences. 2008;82(7-8):348-58.
194 - Yan G, Graham K, Lanza-Jacoby S. Curcumin enhances the anticancer effects of trichostatin a in breast cancer cells. Mol Carcinog. 2012.
195 - Altenburg JD, Bieberich AA, Terry C, Harvey KA, Vanhorn JF, Xu Z, et al. A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone. BMC cancer. 2011;11:149.
196 - Banerjee M, Singh P, Panda D. Curcumin suppresses the dynamic instability of microtubules, activates the mitotic checkpoint and induces apoptosis in MCF-7 cells. The FEBS journal. 2010;277(16):3437-48.
197 - Kizhakkayil J, Thayyullathil F, Chathoth S, Hago A, Patel M, Galadari S. Modulation of curcumin-induced Akt phosphorylation and apoptosis by PI3K inhibitor in MCF-7 cells. Biochem Biophys Res Commun. 2010;394(3):476-81.
198 - Maher DM, Bell MC, O'Donnell EA, Gupta BK, Jaggi M, Chauhan SC. Curcumin suppresses human papillomavirus oncoproteins, restores p53, Rb, and PTPN13 proteins and inhibits benzo[a]pyrene-induced upregulation of HPV E7. Mol Carcinog. 2011;50(1):47-57.
199 - Pan W, Yang H, Cao C, Song X, Wallin B, Kivlin R, et al. AMPK mediates curcumin-induced cell death in CaOV3 ovarian cancer cells. Oncology reports. 2008;20(6):1553-9.
200 - Shi M, Cai Q, Yao L, Mao Y, Ming Y, Ouyang G. Antiproliferation and apoptosis induced by curcumin in human ovarian cancer cells. Cell Biol Int. 2006;30(3):221-6.
201 - Chendil D, Ranga RS, Meigooni D, Sathishkumar S, Ahmed MM. Curcumin confers radiosensitizing effect in prostate cancer cell line PC-3. Oncogene. 2004;23(8):1599-607.
202 - Pichu S, Krishnamoorthy S, Shishkov A, Zhang B, McCue P, Ponnappa BC. Knockdown of ki-67 by dicer-substrate small interfering RNA sensitizes bladder cancer cells to curcumin-induced tumor inhibition. PloS one. 2012;7(11):e48567.
203 - Tian B, Wang Z, Zhao Y, Wang D, Li Y, Ma L, et al. Effects of curcumin on bladder cancer cells and development of urothelial tumors in a rat bladder carcinogenesis model. Cancer letters. 2008;264(2):299-308.
204 - Guo LD, Chen XJ, Hu YH, Yu ZJ, Wang D, Liu JZ. Curcumin Inhibits Proliferation and Induces Apoptosis of Human Colorectal Cancer Cells by Activating the Mitochondria Apoptotic Pathway. Phytotherapy research : PTR. 2012. DOI: 10.1002/ptr.4731
205 - Song G, Mao YB, Cai QF, Yao LM, Ouyang GL, Bao SD. Curcumin induces human HT-29 colon adenocarcinoma cell apoptosis by activating p53 and regulating apoptosis-related protein expression. Braz J Med Biol Res. 2005;38(12):1791-8.
206 - Mosieniak G, Adamowicz M, Alster O, Jaskowiak H, Szczepankiewicz AA, Wilczynski GM, et al. Curcumin induces permanent growth arrest of human colon cancer cells: link between senescence and autophagy. Mechanisms of ageing and development. 2012;133(6):444-55.
207 - Gogada R, Amadori M, Zhang H, Jones A, Verone A, Pitarresi J, et al. Curcumin induces Apaf-1-dependent, p21-mediated caspase activation and apoptosis. Cell cycle. 2011;10(23):4128-37.
208 - William BM, Goodrich A, Peng C, Li S. Curcumin inhibits proliferation and induces apoptosis of leukemic cells expressing wild-type or T315I-BCR-ABL and prolongs survival of mice with acute lymphoblastic leukemia. Hematology. 2008;13(6):333-43.
209 - Bush JA, Cheung KJ, Jr., Li G. Curcumin induces apoptosis in human melanoma cells through a Fas receptor/caspase-8 pathway independent of p53. Exp Cell Res. 2001;271(2):305-14.
210 - Wang L, Shen Y, Song R, Sun Y, Xu J, Xu Q. An anticancer effect of curcumin mediated by down-regulating phosphatase of regenerating liver-3 expression on highly metastatic melanoma cells. Molecular pharmacology. 2009;76(6):1238-45.
211 - Su CC, Wang MJ, Chiu TL. The anti-cancer efficacy of curcumin scrutinized through core signaling pathways in glioblastoma. International journal of molecular medicine. 2010;26(2):217-24.
212 - Liu E, Wu J, Cao W, Zhang J, Liu W, Jiang X, et al. Curcumin induces G2/M cell cycle arrest in a p53-dependent manner and upregulates ING4 expression in human glioma. Journal of neuro-oncology. 2007;85(3):263-70.
213 - Roy AM, Baliga MS, Katiyar SK. Epigallocatechin-3-gallate induces apoptosis in estrogen receptor-negative human breast carcinoma cells via modulation in protein expression of p53 and Bax and caspase-3 activation. Molecular cancer therapeutics. 2005;4(1):81-90.
214 - Meeran SM, Patel SN, Chan TH, Tollefsbol TO. A novel prodrug of epigallocatechin-3-gallate: differential epigenetic hTERT repression in human breast cancer cells. Cancer Prev Res (Phila). 2011;4(8):1243-54.
215 - Gupta S, Ahmad N, Nieminen AL, Mukhtar H. Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells. Toxicology and applied pharmacology. 2000;164(1):82-90.
216 - Singh M, Singh R, Bhui K, Tyagi S, Mahmood Z, Shukla Y. Tea polyphenols induce apoptosis through mitochondrial pathway and by inhibiting nuclear factor-kappaB and Akt activation in human cervical cancer cells. Oncol Res. 2011;19(6):245-57.
217 - Kim YW, Bae SM, Lee JM, Namkoong SE, Han SJ, Lee BR, et al. Activity of green tea polyphenol epigallocatechin-3-gallate against ovarian carcinoma cell lines. Cancer Res Treat. 2004;36(5):315-23.
218 - Kuo PL, Lin CC. Green tea constituent (-)-epigallocatechin-3-gallate inhibits Hep G2 cell proliferation and induces apoptosis through p53-dependent and Fas-mediated pathways. J Biomed Sci. 2003;10(2):219-27.
219 - Huang CH, Tsai SJ, Wang YJ, Pan MH, Kao JY, Way TD. EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Molecular nutrition & food research. 2009;53(9):1156-65.
220 - Lee JH, Jeong YJ, Lee SW, Kim D, Oh SJ, Lim HS, et al. EGCG induces apoptosis in human laryngeal epidermoid carcinoma Hep2 cells via mitochondria with the release of apoptosis-inducing factor and endonuclease G. Cancer letters. 2010;290(1):68-75.
221 - Yamauchi R, Sasaki K, Yoshida K. Identification of epigallocatechin-3-gallate in green tea polyphenols as a potent inducer of p53-dependent apoptosis in the human lung cancer cell line A549. Toxicol In Vitro. 2009;23(5):834-9.
222 - Lee MH, Han DW, Hyon SH, Park JC. Apoptosis of human fibrosarcoma HT-1080 cells by epigallocatechin-3-O-gallate via induction of p53 and caspases as well as suppression of Bcl-2 and phosphorylated nuclear factor-kappaB. Apoptosis. 2011;16(1):75-85.
223 - Harakeh S, Abu-El-Ardat K, Diab-Assaf M, Niedzwiecki A, El-Sabban M, Rath M. Epigallocatechin-3-gallate induces apoptosis and cell cycle arrest in HTLV-1-positive and -negative leukemia cells. Med Oncol. 2008;25(1):30-9.
224 - Kaur M, Mandair R, Agarwal R, Agarwal C. Grape seed extract induces cell cycle arrest and apoptosis in human colon carcinoma cells. Nutr Cancer. 2008;60 Suppl 1:2-11.
225 - Lin YS, Chen SF, Liu CL, Nieh S. The chemoadjuvant potential of grape seed procyanidins on p53-related cell death in oral cancer cells. J Oral Pathol Med. 2012;41(4):322-31.
226 - Kaur M, Agarwal R, Agarwal C. Grape seed extract induces anoikis and caspase-mediated apoptosis in human prostate carcinoma LNCaP cells: possible role of ataxia telangiectasia mutated-p53 activation. Molecular cancer therapeutics. 2006;5(5):1265-74.
227 - Roy P, George J, Srivastava S, Tyagi S, Shukla Y. Inhibitory effects of tea polyphenols by targeting cyclooxygenase-2 through regulation of nuclear factor kappa B, Akt and p53 in rat mammary tumors. Invest New Drugs. 2011;29(2):225-31.
228 - Gu Q, Hu C, Chen Q, Xia Y, Feng J, Yang H. Development of a rat model by 3,4-benzopyrene intra-pulmonary injection and evaluation of the effect of green tea drinking on p53 and bcl-2 expression in lung carcinoma. Cancer Detect Prev. 2009;32(5-6):444-51.
229 - Bhattacharyya A, Choudhuri T, Pal S, Chattopadhyay S, G KD, Sa G, et al. Apoptogenic effects of black tea on Ehrlich's ascites carcinoma cell. Carcinogenesis. 2003;24(1):75-80.
230 - Schwartz JL, Baker V, Larios E, Chung FL. Molecular and cellular effects of green tea on oral cells of smokers: a pilot study. Molecular nutrition & food research. 2005;49(1):43-51.
231 - Tsao AS, Liu D, Martin J, Tang XM, Lee JJ, El-Naggar AK, et al. Phase II randomized, placebo-controlled trial of green tea extract in patients with high-risk oral premalignant lesions. Cancer Prev Res (Phila). 2009;2(11):931-41.
232 - Wang X, Wang R, Hao MW, Dong K, Wei SH, Lin F, et al. The BH3-only protein PUMA is involved in green tea polyphenol-induced apoptosis in colorectal cancer cell lines. Cancer Biol Ther. 2008;7(6):902-8.