A growing body of clinical and experimental evidence has revealed a strong impact of drug resistance on clinical outcomes, especially in cancer therapy, since carcinogenesis is a multi-step, multi-pathway and multi-focal process, which involves a series of epigenetic and genetic alterations [1-3]. In order to solve the serious issue facing clinical treatment, combination therapy is now widely advocated for clinical use and has been shown to have a beneficial effect on patient satisfaction [3, 4]. For instance, 5-fluorouracil (5-FU) and leucovorin with either irinotecan or oxaliplatin have been widely used for the treatment of patients with colorectal cancer [5, 6]. Furthermore, recently, various types of molecular target-based drugs, such as cetuximab and bevacizumab, are being used clinically. Although these continuous efforts to exploit potential combination therapies are ongoing, there is still a growing concern about treatment resistance, disease relapse and side effects of drugs clinically used. Of note, numerous components of edible plants, collectively termed phytochemicals that have beneficial effects for health, are increasingly being reported in the scientific literature and these compounds are now widely recognized as potential therapeutic compounds [1, 2, 4, 7, 8]. In fact, natural product derived substances, especially polyphenolic compounds with very little toxic effects on normal cells, have attracted great attention in the therapeutic arsenal in clinical oncology due to their chemopreventive, antitumoral, radiosensibilizing and chemosensibilizing activities against various types of aggressive and recurrent cancers [1, 8-10].
Apoptosis, or programmed cell death, plays a key role in the development and growth regulation of normal cells, and is often dysregulated in cancer cells [11, 12]. It has been accepted that the aim of anticancer therapy is generally focused on apoptosis induction in premalignant and malignant cells, although other multiple molecular mechanisms such as modulation of carcinogen metabolism, anti-angiogenesis and induction of differentiation are also known to be implicated in its anticancer activity [4, 13]. So far, two principal signal pathways of apoptosis have been identified[11, 12]. The intrinsic mechanism of apoptosis involves a mitochondrial pathway. Apoptosis stimuli destruct mitochondrial membrane structure under the control of Bcl-2 (B-cell leukemia/lymphoma) family, resulting in the release of mitochondrial proteins including cytochrome
Reactive oxygen species (ROS) have been widely believed to play a pivotal role in a wide variety of cellular functions, including cell proliferation and differentiation [3, 11]. Furthermore, oxidative stress, as a result of alterations of redox homeostasis due to an imbalance between ROS production and elimination, is known to be involved in many diseases such as hypoxic injury [11, 18]. Therefore, maintaining ROS homeostasis is crucial for normal cell growth and survival. Generally, cancer cells appear to generate more ROS than do normal cells due to its increased aerobic glycolysis. Furthermore, cancer cells exhibit increased ROS production and altered redox status. Recent studies suggest that these biochemical characteristics of cancer cells can be exploited for therapeutic benefits [3, 18]. Especially, tumors in advanced stage frequently exhibit multiple genetic alterations and high oxidative stress, suggesting that it is possible to preferentially eliminate these cells by pharmacological ROS insults. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance [3, 18]. Thus, abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications [2, 3, 18, 19]. Indeed, it has been known that altered redox status is closely associated with apoptosis induction in various cancer cells [2, 3, 18, 19]. Collectively, manipulating ROS levels by redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells.
Polyphenolic compounds such as flavonoids and curcumin have been shown to induce apoptosis in various malignant cells including solid tumors and hematologic malignant cells [1, 2, 7-9, 20-22]. Interestingly, the mechanisms underlying the apoptosis induction, associated with their antitumoral, chemopreventive and chemotherapeutic activities, have been shown to be implicated in alteration of redox status, since polyphenolic compounds are well known to possess both antioxidant and prooxidant activity [1, 2, 7, 8, 10, 20, 22-26].
In this chapter, we will highlight the recent advances on the cancer preventative activities of the polyphenolic compounds, including flavonoids such as anthocyanins, and
2. Cancer preventative activities of the polyphenolic compounds, anthocyanins, Vitex, and curcumin
2.1. Resource and chemistry of anthocyanins, Vitex, and curcumin
The most abundant flavonoid constituents of fruits and vegetables are anthocyans (i.e. anthocyanins (glycosides), and their aglycones, anthocyanidins) that confer bright red or blue coloration on berries and other fruits and vegetables [8, 20]. Anthocyanins are especially interesting with respect to other flavonoids because they occur in the diet at relatively high concentrations. The daily intake of anthocyanins in the US diet has been suggested to be 180-255 mg/day, in contrast, the daily intake of most other dietary flavonoids, including genistein, quercetin and apigenin, is estimated to be only 20-25 mg/day . Anthocyanidins are a diphenylpropane-based polyphenolic ring structure, and are limited to a few structure variants including cyanidin, delphinidin, malvidin, pelargonidin, peonidin and petunidin (Figure 1), with a distribution in nature of 50%, 12%, 12%, 12%, 7%, and 7%, respectively, and they present almost exclusively as glycosides, anthocyanins . Furthermore, epidemiological evidence has demonstrated that consumption of fruits and berries has been associated with decreased risk of developing cancer .
Curcumin, a hydrophobic polyphenol, also known as turmeric, is a major bioactive ingredient extracted from the rhizome of the plant
2.2. Involvement of altered redox status in apoptosis induction triggered by polyphenolic compounds
It has been demonstrated that anthocyanin-rich extracts from berries and grapes, and several pure anthocyanins and anthocyanidins, exhibit pro-apoptotic effects in multiple cell types such as colon [23, 36], breast [37, 38], prostate [39, 40], and leukemia cancer cells [10, 41]. They induce apoptosis through both intrinsic (mitochondrial) and extrinsic (Fas) pathways. In the intrinsic pathway, the treatment of cancer cells with anthocyanin results in destabilization of the mitochondrial membrane, cytochrome
Intriguingly, a good correlation has been found between anthocyanin chemical structure and chemoprotective activity. Indeed, several lines of evidence have shown that the number of hydroxyl groups on the B-ring of anthocyanidins is associated with the potency of prooxidative [45-47], apoptotic induction , anti-transformation , as well as anti-oxidative activities [1, 8]. For instance, delphinidin and cyanidin that possess
We have been interesting the effects of naturally derived flavonoids on the growth of various types of cancer cells. Of those, we have demonstrated that Vitex exhibits cytotoxic activities against various types of solid tumor cells, such as KATO-III (a human gastric signet ring carcinoma cell line), COLO 201 (a human colon adenocarcinoma cell line), MCF-7 (a human breast carcinoma cell line) . More interestingly, no apparent cytotoxicity was observed in non-tumor cells, such as human uterine cervical canal fibroblast (HCF) and human embryo fibroblast (HE-21) when treated with concentrations showing significant cytotoxicity in tumor cells, suggesting a selective cytotoxic activity against tumor cells . We further demonstrated that Vitex induced apoptosis accompanied by an accumulation of intracellular ROS along with the decrease in the levels of intracellular GSH in KATO-III cells . At the same time, our experimental data demonstrated a decrease in the amount of Bcl-2, Bcl-xL and Bid proteins; an increase in Bad protein; activation of caspase-8, -9 and -3; a leakage of cytochrome
Curcumin has emerged worldwide as a potent therapeutic substance for treating diverse human diseases including various types of cancer, such as leukemia, colon cancer and pancreatic cancer [7, 25, 35, 55, 56]. Although the precise mode of action of this compound is not yet elucidated, studies have shown that chemopreventive action of curcumin might be due to its ability to induce apoptosis through multiple signaling pathways, including intrinsic and extrinsic pathways as well as ER stress pathway [7, 57]. It has been suggested that curcumin-induced apoptosis is associated with ROS production and/or oxidative stress in cancer cells, in spite of its normal antioxidant capacity [7, 57]. Indeed, it has been demonstrated that curcumin can generate ROS as a prooxidant in the presence of copper in HL-60 cells, resulting in DNA damages and apoptotic cell death . Furthermore, the prooxidant action of curcumin may be related to the conjugated β-diketone structure of this compound . Kuo et al. also demonstrated that curcumin induced a dose- and time-dependent apoptotic cell death in the same cells, concomitant with a decrease of Bcl-2 expression . However, the antioxidants, NAC, L-ascorbic acid, alpha-tocopherol, catalase and superoxide dismutase, all effectively prevented curcumin-induced apoptosis, suggesting that curcumin-mediated apoptosis was closely related to the increase in intracellular ROS . Besides hematopoietic cancer cells, curcumin-mediated apoptosis in human breast epithelial cells (H-ras MCF10A) involved generation of ROS as well as down-regulation of Bcl-2 and up-regulation of Bax, suggesting redox signaling as a mechanism responsible for curcumin-induced apoptosis in these cells . Syng-Ai et al. also demonstrated that curcumin-induced apoptosis in human breast tumor cell lines (MCF-7, MDAMB) and HepG2 cells is also mediated through the generation of ROS, and that depletion of glutathione by buthionine sulfoximine (BSO) promoted the increased generation of ROS, thereby further sensitizing the cells to curcumin . Interestingly, curcumin had no cytocidal effect on normal rat hepatocytes, because of no superoxide generation . These observations suggest that curcumin with broad biological actions could be developed into an effective chemopreventive and chemotherapeutic agent based on its ability to modulate intracellular redox status. However, the use of curcumin as a therapeutic agent has met with considerable skepticism, since as much as 75% of curcumin is excreted in the feces  and also undergoes repaid inactivation by glucuronidation , similar to metabolisms of flavonoids . Recently, in order to increase its metabolic stability, numerous approaches have been undertaken, such as generating the fluoro-analog of curcumin termed Diflourinated-Curcumin (referred to as CDF) that exhibits increased metabolic stability [64, 65]. Furthermore, the CDF has been found to exhibit superior growth inhibitory properties against cancer cells to the parental compound curcumin [56, 64, 65].
3. Potential future application of polyphenolic compounds, alone or in combination with, anticancer drugs
As mentioned in the previous section, the deregulation and sustained activation of multiple tumorigenic pathways are typically implicated in cancer development and progression with locally advanced and aggressive nature. Consequently, the use of therapeutic agents acting on different deregulated gene products, alone or in combination therapy, may represent a potentially better strategy than the targeting on one specific oncogenic product to overcome treatment resistance and prevent cancer development and disease recurrence [2-4, 7]. So far, one of the most successful models for combinatory cancer therapies is all-
The successful clinical efficacy of ATO in the treatment of APL patients has led to investigations on exploring potential treatment applications for other malignancies, including ATO-resistant hematopoietic cancer and solid tumors [75, 76]. In order to further extend our previous study and promote the clinical application of arsenite, we have been seeking to explore potential candidate agents, which are expected to not only potentiate the efficacy of ATO but also possibly reduce its dosages . In this regard, using HL-60 cells which are reported to show resistance to arsenite, we found that delphinidin showed selective cytotoxic effects on the cells, but minimal effects on PBMNC, and sensitized the cells to arsenite, resulting in the enhancement of arsenite cytotoxicity (Yuan et al. manuscript in preparation). Therefore, our experimental data suggest that sensitization of HL-60 cells to arsenite achieved by the combination with delphinidin could benefit a reduced dosages of arsenite in clinical application, contributing to minimize side effect. The clinical trial planning is now underway.
Of note, it is well known that oxidative stress is involved in the mechanisms underlying the therapeutic efficacy of arsenite and plays a major role in the toxicity of arsenite [4, 13, 77]. In fact, in order to maximally exploit effective ROS-mediated cell death without causing significant toxicity to normal cells, redox-based drug combination strategies have been proposed [3, 11, 18]. Based on the strategies, ROS-generating reagents including natural products derived substances, especially phenolic compounds, have received much attention due to their cytocidal effects on tumor cells but little on normal cells. In this regard, like the cytocidal effects of cyanidin-3-rutinoside on leukemia cells , delphinidin 3-sambubioside has also been demonstrated to induce apoptosis in HL-60 through ROS-mediated mitochondria pathway , suggesting these anthocyanins are good candidates for ROS-generating reagents, thereby possibly potentiate the action of ATO. Indeed, quercetin and/or genistein are flavonoid with multiple biochemical effects such as downregulation of phosphoinositide 3-kinase/Akt signaling pathway and NF-κB transcription factor activity [79, 80], tyrosine kinase inhibition [81, 82]. Furthermore, both quercetin and genistein have been reported to selectively potentiate ATO-induced apoptosis via ROS generation resulted from intracellular GSH depletion, and activation of intrinsic and extrinsic apoptotic pathway in human leukemia cell lines such as HL-60, U937 and THP-1, but not in phytohemagglutinin-stimulated non-tumor peripheral blood lymphocytes [24, 83]. These results thus suggest that these flavonoids might be used to increase the clinical efficacy of ATO. Similar to flavonoids, subcytotoxic concentrations of curcumin also has been demonstrated to stimulate ROS production and potentiate apoptosis induction by ATO in leukemia cell lines via deregulation of Akt phosphorylation .
With these considerations in mind, a lot of preclinical and clinical trials have been carried out. For instance, we recently reported for the first time that 5-FU in combination with Vitex achieved an enhanced cytocidal effect on COLO 201 cells, but lesser cytotoxic effect on human PBMNC . It has also been demonstrated that delphinidin induces apoptosis and inhibited NF-κB signaling in prostate tumor cells in vitro and in a human prostate tumor xenograft in nude mice in vivo . Furthermore, twenty-five colon cancer patients without receiving prior therapy and surgery consumed 60 g/day (20 g/3x/day) of black raspberry powder daily for 2–4 weeks. Biopsies of normal-appearing and tumor tissues were taken from these patients before and after berry treatment. Intake of berries reduced proliferation rates and increased apoptosis in colon tumors but not in normal-appearing crypts . On the other hand, supplementation of anthocyanins in the diet of cancer patients receiving chemotherapy did not result in increased inhibition of tumor development when compared to chemotherapy alone . These conflicting findings suggest that a large scale of clinical trial is needed.
A phase I clinical trial has shown that quercetin, another one of flavonoids, can be safely administered to patients with ovarian cancer or hepatoma by intravenous injection of bolus at a dose of 1400 mg/m2. Moreover, the evidence of antitumor activity was seen in the clinical trial based on sustained fall in serum CA 125 levels, which is proposed for the use as a surrogate marker of response . Furthermore, similar to our previous report , CDF (a difluorinated analog of curcumin), alone or in combination with 5-FU and oxaliplatin, was more potent than curcumin alone in reducing the number of chemoresistant HCT-116 and HT-29 colon cancer cells expressing CD44 and CD166 stem cell-like markers . Concomitantly, cell growth inhibition, apoptosis induction and disintegration of colonospheres in these colon cancer cells were also observed in the study . Moreover, clinical trials have confirmed the safety and feasibility to use curcumin in combination therapy with current chemotherapeutic treatments . More recent results from a phaseI/II study on 21 advanced pancreatic cancer patients with gemcitabine-based chemotherapy have indicated that the median overall survival time of the patients after a treatment with curcumin plus gemcitabine or gemcitabine/S-1 combination was 161 days and 1-year survival rate of 19% (95% confidence interval) . Among eighteen evaluable patients, no patients experienced a partial or complete response and five patients (28%) demonstrated stable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) .
Although many encouraging results of in vitro and in vivo studies suggest polyphenolic compounds as a promising candidate for cancer therapy, either alone or in combination with current anticancer drugs, the therapeutic applications of these compounds in humans are limited by their high metabolic instability as well as poor absorption and bioavailability [1, 7, 8, 20, 87]. In this regard, the selective delivery of nanotechnology-based formulations of these polyphenolic compounds to tumors, alone or in combination with other anticancer drugs, has been of great interest [7, 26, 88]. For instance, pegylated liposomal quercetin was shown to significantly improve its solubility and bioavailability and be a potential application in the treatment of tumor based on a study using CT26 (a mouse colorectal carcinoma cell line), LL/2 (Lewis lung cancer cell line) and H22 (a hepatoma cell line) xenograft mice . Furthermore, diverse curcumin formulations have been developed with different nanotechnology consisting of its encapsulation or conjugation with nanoparticles, polymeric micelles or liposomes to improve its stability, bioavailability and specific and sustained delivery into cancer cells and, consequently, its anticarcinogenic effects . In particular, the systemic administration of gemcitabine plus polymeric micelle-encapsulated curcumin formulation enhanced greater bioavailability in plasma and tissues as compared to that of free curcumin in xenograft models of human pancreatic cancer established in athymic mice . In consequence, the combinatory administration efficiently block tumor growth and metastases in this animal model of pancreatic cancer. Furthermore, an inhibition of NF-κB and its targeted genes are implicated in the tumor growth inhibition . Therefore, the use of nanotechnology-based formulations of polyphenolic compounds and their novel chemical analogs probably represents a potential alternative strategy of great clinical interest for overcoming the high metabolic instability and poor bioavailability of these compounds, which are among the principal factors limiting their therapeutic applications.
A striking global research on substances derived from natural products including polyphenolic compounds is being explored to understand the detailed mechanisms of their chemopreventive, antitumoral and chemosensibilizing activities against various types of aggressive and recurrent cancers. Besides the involvement of altered redox status in apoptosis induction triggered by these compounds, anti-inflammatory effects, anti-angiogenesis, anti-invasiveness and induction of differentiation are well known to be implicated in their broad biological functions. It is worthy of note that flavonoids have been revealed to inhibit the function of ATP-binding cassette transporters such as multidrug resistance-associated proteins as well as P-glycoprotein , similar to our recent study . On the other hand, a recent study demonstrated that berry anthocyanins, such as cyanidin-3-galactosidee, and cyanidin-3-glucoside as well as peonidin-3-glucosid, exhibit affinities for the efflux transporters breast cancer resistance protein (BCRP) and consequently may be actively transported out of intestinal tissues and endothelia . However, the same report also demonstrated that some berry anthocyanins and anthocyanidins, such as delphinidin, cyanidin and cyanidin-3-rutinoside, act as BCRP inhibitor, while some of them, such as malvidin, malvidin-3-galactoside and petunidin, exhibited bimodal activities serving as BCRP substrates and inhibitors at low concentrations and high concentrations, respectively . These findings suggest that a variety of biological activities of anthocyanins and anthocyanidins may be attributed in part to their inhibitory effects on those drug transporters, paradoxically, may be abolished as a result of efflux through those transporters. These findings also raised a pharmacological and pharmaceutical concern about formulatability of the dietary constituent, and warn us against the casual use of herbs and/or other botanicals in cancer patient care.
This work was supported in part by grants from Japan China Medical Association to B.Y. This work was also supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology and by the Promotion and Mutual Aid Corporation for Private Schools of Japan. The authors thank Dr. Chieko Hirobe for encouraging suggestions and arranging sample supply, and Dr. Yamato Kikkawa for providing HCC cell lines for this study.
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