Monoterpene and colorectal cancer.
Abstract
Colorectal cancer (CRC) is one of the most common cancers in the world. Around 90% of CRC deaths are caused by metastasis, and systemic chemotherapy is the last hope for patients with unresectable metastases of CRC. Although recent systemic chemotherapy advances have prolonged survival in patients with unresectable CRC, the effectiveness, cost, and side effects of the chemotherapeutic agents still need to improve. The use of plant-, microbial-, or fungal-derived natural products for medical benefits is playing an important role globally, such as in anti-cancer drugs and antibiotics.
Keywords
- fatty acid synthase inhibitor
- monoterpene
- colorectal cancer
- chemotherapy
- cerulenin
1. Introduction
Colorectal cancer (CRC) is one of the most common cancers in the world, and about 90% of CRC deaths are caused by metastasis, not by primary solid tumors [1]. Despite recent advances, systemic chemotherapy for metastatic disease is considered palliative, and long-term survivors are rarely seen treated only by chemotherapy [2]. Natural products are the most successful strategy to discover new agents used in anti-cancer therapy and more than two-thirds of the drugs used in cancer treatment [3]. A large number of studies have focused on the efficacy of essential oils and their chemical constituents as bioactive new products [4], especially cancer treatment [5, 6]. The essential oils are a mixture of volatile lipophilic substances: monoterpenes, sesquiterpenes, and phenylpropanoids. These substances have many biological activities such as analgesic, anti-convulsant, anti-inflammatory [6, 7, 9], and anti-tumor activities [10–14]. Monoterpenes of several essential oils from plants possess medical benefits. The various monoterpenes, such as limonene, geraniol, 1,8-cineole, and perillyl alcohol (POH), are effective for CRC in in vitro and animal experiments [15].
2. Monoterpenes
Terpenes are the largest class of plant-derived secondary metabolites, and they are the main component of essential oils [16, 17]. Monoterpenes are the largest class of terpenes [18]. The therapeutic properties of monoterpenes are anti-allergic, anti-inflammatory, anti-cancer, and so on [19]. The basic structure of monoterpenes consists of two isoprene units (C5H8)2. Monoterpenes exist in many forms in nature, such as hydrocarbons, alcohols and their glycosides, ethers, aldehydes, ketones, carboxylic acids, and esters [15]. Monoterpenes are classified as acyclic, monocyclic, and bicyclic according to the ring formation. The important acyclic monoterpenes, which have anti-tumor effects, are myrcene and geraniol [20]. The important monocyclic monoterpenes with anti-tumor effects are linalyl acetate, camphor, thymol, carvacrol, POH, d-limonene, and many others. POH and d-limonene are said to inhibit the development of several types of carcinomas as they were in Phase I and II clinical testing, respectively [21, 22]. The bicyclic monoterpenes that have anti-tumor effects are 1,8-cineole (eucalyptol), and α- and β-pinene [23, 24].
3. Monoterpene and colorectal cancer
In this chapter, we reviewed monoterpenes with anti-CRC activity. The monoterpenes presented in this chapter were selected with reference to effects shown in specific experimental models for evaluation of anti-tumor activity and/or by complementary studies aimed to elucidate mechanisms of action shown in Table 1.
Compound | Mechanism | Animal/cell line tested | IC50, etc | Reference |
---|---|---|---|---|
Acyclic | ||||
Geraniol | Cell cycle arrest/5FU synergy |
Caco-2 | 200 μM (Caco-2 IC30) | [26] |
Cell cycle arrest | Caco-2 | 400 μM(70% inhibition) | [27] | |
ERK1/2 inactivation | Caco-2 | 400 μM(60% reduction of PKC activity) | [28] | |
Synergistic with 5FU | TC-118/Swiss nu/nu mouse | 5FU 20 mg/kg, geraniol 150 mg/kg |
[29] | |
Thymidylate synthase reduction | 53% tumor reduction | |||
Monocyclic | ||||
Alpha terpineol |
Cell cycle arrest, apoptosis |
HCT-116 (p53+/+, −/−) | 1 mM | [30] |
Linalyl acetate | Alpha terpineol + linalyl acetate + camphor | |||
Camphor | ||||
Carvacrol | Anti-oxidant activity | Caco-2, K562, HepG2 | 150–200 μM (IC50 of K562) | [31, 32] |
Cytotoxic effect | Caco-2 | 600 μM (IC50) | [34] | |
Anti-oxidant activity | DMH/DSS carcinogenesis rat | 50 mg/kg | [35] | |
Thymol | Cytotoxic effect | Caco-2 | 700 μM (IC 50)) | [34] |
Apoptosis | HL60 | 75 μM(12 h), 50 μM(24 h) | [36] | |
Thymoquinone (TQ) |
Apoptosis, Wnt signal |
ApcMin rat | 375 mg/kg BW 12 w (polyp decrease) |
[38] |
Apoptosis | HCT-116 xenograft | 5 mg/kg (3 times/week ip) | [39] | |
ERK JNK, apoptosis by ROS |
Caco-2 | 15.0 μM (IC50 24 h) | [40] | |
HCT-116 | 30 μM (IC50 24 h) | |||
LoVo | 38 μM (IC50 24 h) | [40] | ||
DLD-1 | 42 μM (IC50 24 h) | |||
HT-29 | 110 μM (IC50 48 h) | |||
Nanoparticle with poly(sodium undecylenyl-valinate) |
MDA-MB-231 | viability 16.0 ± 5.6%(96 h) | [41] | |
Protection from Doxorubicin |
Mouse with DOX(20 mg/kg) | TQ (8 mg/kg p.o.) protect cardiotoxicity | [42] | |
Synergistic with Doxorubicin |
HT-29 | 46.8 μM to 39.0 μM (with DOX) | [43] | |
D-limonene | Blood orange volatile | SW480, HT-29 | 100 ppm, 74.2% reduction of SW480 |
[44] |
Ornithine decarboxylase (ODC) | Azoxymethane, F344 rat |
0.5% d-limonene decreases ACF formation | [45] | |
Apoptosis by Akt inactivation | colon cancer (LS174T) | 3.2 mM viability 30% decrease | [46] | |
Clinical trial phase I and II |
CRC patients | 0.5 mg/m2/day | [47, 48] | |
Perillyl alcohol |
Protein isoprenylation | HT-29 | 50 μM (IC50) | [49] |
Apoptosis | Azoxymethane | 2 g/kg decrease cancer incidence to 1/3 |
[50] | |
G1 arrest | HCT-116 | 0.5 mM (IC50) | [51] | |
Clinical trial | CRC patients | 1200–1600 mg/m2/day | [52–56] | |
Bicyclic | ||||
1,8-cineole | Akt inactivation | RKO | 50 mg/kg reduced tumor weight as 1/3 |
[24] |
3.1. Geraniol
Geraniol is an acyclic monoterpenes. Geraniol is one of the main components of geranium oil, and its content is about 20% [25]. Geraniol shows a cytotoxic effect in Caco-2 colon cancer cells [26–28]. Geraniol decreases the expression of p44/p42 ERK and has an anti-tumor effect in Caco-2 cells [28]. In addition, geraniol has a synergistic anti-tumor effect combined with 5-fluorouracil in TC-118 human colorectal tumors [29].
3.2. Alpha terpineol, linalyl acetate, and camphor
Alpha terpineol, linalyl acetate, and camphor are monocyclic monoterpenes, and they are the bioactive components of Lebanese sage (
3.3. Carvacrol
Carvacrol is a monocyclic monoterpene constituent of essential oils produced from the aromatic plant
3.4. Thymol
Thymol is a monocyclic monoterpene and can be found in the oil of thyme. Thymol presents a cytotoxic effect in several cell lines, such as HepG2, V79, and Caco-2 human colon cancer cells [35]. The cytotoxic effect of thymol on human leukemia cell HL-60 appears to be associated with induction of cell cycle arrest at sub G0/G1 phase and apoptotic cell death. Thymol induced apoptosis in HL-60 cells involves both caspase-dependent and caspase-independent pathways [36].
3.5. Thymoquinone
Thymoquinone (2-methyl-5-isopropyl-1,4-benzoquinone) is a monocyclic monoterpene present in the seed oil of the plant
3.6. D-limonene
Limonene is a monocyclic monoterpene, and it is a major constituent of citrus oils. It has optical isomers, d-limonene and l-limonene, and d-limonene has a more lemon-like odor and therapeutic effects. D-limonene is contained in citrus volatile oil, and the citrus volatile oil induces apoptosis and has an anti-angiogenic effect against colon cancer SW480 and HT-29 [44]. D-limonene also inhibited the development of colonic aberrant crypt foci (ACF) induced by azoxymethane in F344 rats, which suggests that this monoterpenoid might be a chemopreventive agent for colonic carcinogenesis in rats [45]. D-limonene suppressed the viability of LS174T colon cancer cells in a dose-dependent manner and caused a dose-dependent apoptotic cell death. D-limonene decreased the levels of Akt pathway, activated caspase-3 and caspase-9 and PARP cleavage in a dose-dependent manner [46]. A group of 32 patients with solid tumors registered and completed Phase I study of administration of d-limonene orally. The maximum tolerated dose was 8 g/m2 per day, and nausea, vomiting, and diarrhea were dose-limiting factors [47]. Three individuals with colorectal carcinoma with d-limonene suspended progression of the disease for over 6 months [47]. D-limonene at a dosage of 0.5 g/m2/day was able to halt progression of cancer for 9 months in a patient diagnosed with locally advanced mucinous cystadenocarcinoma of the appendix. A patient with presacral recurrence of an adenocarcinoma in the sigmoid colon experienced a minor reduction (<50%) in tumor size at a dose of 0.5 g/m2/day for 12 months. Another patient with local retrovesical recurrence of colorectal adenocarcinoma remained stabilized on 1 g/m2/day (2 g/day) for 7.5 months [47, 48].
3.7. Perillyl alcohol (POH)
POH is a monocyclic monoterpene, and it is derived from limonene. POH is a naturally occurring dietary monoterpene isolated from the essential oils of lavender, peppermint, and other plants. It has an anti-tumor effect in several cancer cell lines including the HT-29 colon cancer cell line [49]. Dietary POH at 1 or 2 g/kg greatly reduced the incidence and the number of invasive adenocarcinomas of the colon of rats injected with azoxymethane [50]. To establish the molecular mechanisms of POH, cell cycle and cell cycle regulatory proteins were studied in HCT-116 human colon cancer cells. POH exerted a dose-dependent inhibitory effect on cell growth correlated with a G1 arrest [51]. Phase I and II clinical trials using POH were started [21, 22, 52–55]. In seven Phase I clinical trials, POH was administered orally to cancer patients with advanced malignancy. POH was given in divided doses ranging from 2,400 to 16,200 mg per day (equivalent to approximately 40–270 mg/kg). Treatment duration varied with each patient but was generally between 2 and 9 months. Nausea, vomiting, eructation, and satiety were dose-limiting factors in several of these trials [21]. Meadows et al. conducted Phase II study in patients with metastatic CRC [56]. The authors found that oral POH administration did not have clinical anti-tumor activity when used for patients with advanced colorectal carcinoma, despite preclinical evidence of anti-cancer activity. Instead of oral administration, POH was administered through nasal inhalation to recurrent glioma patients, and these studies not only demonstrated clinical activity of POH but also revealed that long-term intranasal inhalation of the compound was very well tolerated over several years of daily use [21, 57, 58].
3.8. 1,8-cineole (eucalyptol)
1,8-cineole (eucalyptol) is a bicyclic monoterpene, which comprises up to 90% of the essential oil of some species of the generic product Eucalyptus oil. 1,8-cineole has several effects such as anti-inflammatory, anti-oxidant, and anti-atherosclerotic activity in vitro and in vivo. 1,8-cineole has a cytotoxic effect in Hep G2, HeLa, MOLT-4, K-562, and CTVR-1 cell lines [59]. 1,8-cineole was reported to have moderate anti-oxidant and cytotoxic properties and pronounced analgesic and anti-tumor activity [60]. Murata et al. showed that the human CRC cell line RKO expressed phosphoserine 473-Akt constitutively and treatment with 1,8-cineole dephosphorylated Akt. 1,8-cineole treatment activated p38 and dephosphorylated Akt, which induced caspase-3 cleavage and resultant cleavage of PARP and finally caused apoptosis. In a xenograft mouse model, 1,8-cineole therapy showed tumor shrinkage [24].
3.9. α- and β-pinene
α- and β-pinene are bicyclic monoterpenes. They are natural compounds isolated from pine needle oil. Bhattacharjee and Chatterjee [61] promoted the identification of proapoptotic, anti-inflammatory, anti-proliferative, anti-invasive, and potential anti-angiogenic activities of α-pinene, β-pinene, d-limonene, and geraniol by employing a dual reverse virtual screening protocol. The anti-tumor activity of α-pinene on the BEL-7402 hepatoma cell line in vitro and in vivo and the mechanisms involved were investigated. The results showed that liver cancer cell growth was inhibited obviously in vitro and in vivo: Chk1 and Chk2 levels were up-regulated; and Cyclin B, CDC25, and CDK1 levels were down-regulated [62].
3.10. Conclusion of monoterpenes
Several studies have shown in vitro and in vivo anti-tumor activity of monoterpenes derived from many essential oils obtained from plants. This chapter shows that many monoterpenes are being examined for in vitro and in vivo anti-tumor activity of CRC. In addition, two of the monoterpenes, d-limonene and POH, were moved on to Phase I and II clinical trials, which indicates the safety of monoterpenes for clinical use. There are many monoterpenes that show anti-tumor effects in vitro and in vivo, and with additional research some monoterpenes act to inhibit the proliferation and to induce tumor cell death in clinical use.
4. Fatty acid synthase (FASN) inhibitors
Fatty acid synthase (FASN), the key enzyme of
Compound | Mechanism | Animal/cell line tested | IC50, etc | Reference |
---|---|---|---|---|
Cerulenin | Akt inhibition | Colon 26 liver metastasis/Balb-c mouse |
30 mg/kg reduces 50% of liver metastasis | [93] |
Akt inhibition, synergistic with oxaliplatin | RKO/xenograft in SCID mouse | Cerulenin 15 mg/kg, oxaliplatin 2.5 mg/kg | [94] | |
Malonyl-co A independent apoptosis | RKO | 10 μg/ml | [101] | |
C75 | Malonyl-co A independent apoptosis | RKO | 10 μg/ml | [101] |
Orlistat | ER stress, synergistic with thapsigargin | HT-29 | Orlistat 25 μM, thapsigargin 25 nM | [114] |
Luteolin | Cell cycle arrest, apoptosis | HT-29 | 60 μM 83% decrease of survival at 72 h |
[121] |
S1P, ceramide, Akt inhibition |
Caco-2 | 100 μM more than 50% decrease at 48 h |
[122] | |
Synergic effect with aspirin | DMH rat carcinogenesis | 0.2 mg/kg/weekly for 15 weeks | [123] | |
iNOS, COX2 inhibition | Mouse, azoxymethane administration | 1.2 mg/kg orally | [124] | |
β-catenin, GSK-3-β, cyclin D1 inhibition |
HCT-15 | 100 μM (IC50) | [125] | |
EGCG | Cell proliferation, apoptosis | HCT-116 | 100 μM 98.4% decrease of survival at 48 h |
[131] |
VEGF/VEGFR axis | SW837 mouse xenograft | 0.01% EGCG drinking | [133] | |
HES1, Notch 2 | HT-29 mouse xenograft | 5 mg/kg intragastrically | [135] | |
Clinical trials | Polyp relapse decreasing | 1.5~2.5 g green tea extract/daily | [137] |
In this chapter, we reviewed FASN inhibitors with anti-CRC activity. The FASN inhibitors presented in this chapter were selected with reference to effects shown in specific experimental models for evaluation of anti-tumor activity and/or by complementary studies aimed to elucidate mechanisms of action shown in Table 2.
4.1. Cerulenin
Cerulenin is the first-known FASN inhibitor, which is isolated from the culture filtrate of the fungus
4.2. C75
C75 is a cerulenin-derived, semi-synthetic FASN inhibitor lacking cerulenin’ s reactive epoxy group [98], and C75 is more chemically stable than cerulenin [98]. C75 has significant anti-tumor effects against many types of cancer cells, such as the human breast [98], prostate [91], and ovary [99] as well as renal carcinoma in xenograft animal models [100]. Li et al. reported that both C75 and cerulenin produce rapid, potent inhibition of DNA replication and S-phase progression in human cancer cells, as well as apoptotic death. They also revealed that these FASN inhibitors reduce cyclin A-, B1-associated kinase activities, and p53, p21 accumulation which cause growth arrest at G1 and G2 [101]. Cerulenin and C75 were useful against p53 mutations [101]. They discussed that accumulation of malonyl-CoA was independent of apoptosis induction, and they estimated that the effect of these agents has resulted from product depletion [101].
4.3. C93
In addition to inhibiting FASN, C75 stimulates fatty acid oxidation by activating carnitine
4.4. Orlistat
Orlistat is an anti-obesity drug approved by the US Food and Drug Administration. Orlistat is also reported to inhibit FASN [107]. Orlistat is the only long-term option for obesity treatment in the United States, and it is the only approved weightloss drug in Europe [108]. Orlistat is a synthetic hydrogenated derivative of lipstatin, produced by the fungus
4.5. Luteolin
Luteolin, 3′,4′,5,7-tetrahydroxyflavone, is found in a variety of vegetables, fruits, and medicinal herbs. Luteolin has been shown to function as an anti-oxidant, anti-inflammatory, and anti-cancer agent [118]. Additionally, luteolin induces cell cycle arrest and apoptosis in the liver and lung cancer cell lines [119, 120]. Lim do et al. indicated that luteolin inhibited HT-29 cell proliferation by inducing cell cycle arrest and apoptosis [121]. Luteolin exerts toxic effects on colon cancer cells by inhibiting both S1P biosynthesis and ceramide traffic, inhibiting Akt activation [122]. The supplementations of luteolin in addition to aspirin in the treatment of DMH-induced carcinogenesis in rats reflect a better effect than the use of aspirin alone [123]. Luteolin suppresses both iNOS and COX-2 expressions and plays an anti-inflammatory role during the administration of azoxymethane in mice [124]. Luteolin decreased the expressions of β-catenin, phospho GSK-3-β, and cyclin D in HCT-15 cells. Luteolin also promoted cell cycle arrest at the G2/M phase and induced apoptosis in HCT-15 cells. Furthermore, Western blot analysis showed that luteolin treatment enhanced the expression of Bax and caspase-3, whereas the expression of Bcl-2 was suppressed [125].
4.6. Epigallocatechin gallate (EGCG)
EGCG, which is green tea polyphenol, inhibits the activity of FASN [126, 127]. EGCG induces apoptosis in human breast and prostate cancer cells [128–130]. It is also the major biologically active component that inhibits cell proliferation and induces apoptosis in HCT-116 and SW-480 human CRC cells [131]. EGCG suppresses FASN expression and downstream PI3K/Akt pathway [132]. EGCG activates stress signals, such as c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK), and induces apoptosis in CRC cell lines [131]. EGCG has also been reported to inhibit the growth of human CRC cells in subcutaneous xenograft models [133–135]. Maruyama et al. revealed that EGCG strongly reduces liver metastasis of human CRC in SCID mice [136].
Epidemiologically, green tea consumption of >10 cups daily reduced CRC risk in Japanese [137]. A double-blind, placebo-controlled study with green tea in Italian patients showed a successful prevention of prostate cancer. The progression of prostate cancer in men with high-grade prostate intraepithelial neoplasia, the main premalignant lesion of prostate cancer, was significantly prevented by oral administration of green tea catechins, 600 mg/d for 1 year [138]. Shimizu et al. conducted a randomized trial to determine the preventive effect of green tea extract (GTE) supplements on metachronous colorectal adenomas by raising green tea consumption in the target population from an average of 6 cups (1.5 g GTE) daily to 10 cups equivalent (2.5 g GTE) by supplemental GTE tablets. To 136 patients with colorectal polyp resection, they performed colonoscopy to confirm no polyps in the colorectum 1 year later. Then they randomized into two groups, i.e., GTE group and control group. The incidence of metachronous adenomas at the endpoint colonoscopy was 31% (20 of 65) in the control group and 15% (9 of 60) in the GTE group (relative risk, 0.49; 95% confidence interval, 0.24–0.99;
4.7. Triclosan
Triclosan has the U.S. Food and Drug Administration approval as a bactericide in personal hygiene products (toothpaste, mouth rinse, hand wash, soaps, and deodorant) and has been used since 1968 [77]. Triclosan has an established safety profile with minimal toxicity in rats, dogs, baboons, and humans; no significant weight loss is associated with triclosan treatment; and triclosan is not a genotoxic or mutagenic compound [77]. Triclosan has excellent oral bioavailability and stability in plasma [140]. Triclosan also acts as a FASN inhibitor to inhibit enoyl reductase of FASN [141], and it showed chemo-preventative activity in a rat mammary carcinogenesis model [142]. Similarly, treatment of male rats with triclosan did not induce significant changes in body weight at any of the test doses [143]. Recently, Sadowski et al. evaluated triclosan as a repurposed drug against prostate cancer cells and compared its activity to C75 and orlistat, two well-known FASN inhibitors [77, 144]. In this comparative study, Sadowski et al. discovered that triclosan is a superior alternative to C75 and orlistat in inducing cell death of prostate cancer cells through inhibition of FASN [77].
4.8. Capsaicin
Capsaicin (trans-8-methyl-
4.9. Curcumin
Curcumin is a hydrophobic polyphenol derived from the rhizome of
4.10. Newly developed agents
TVB-3567 [80] and TVB-3166 [81] are newly developed FASN inhibitors provided from 3-V Biosciences, which inhibit many kinds of cancer cell lines, such as CRC cell lines, COLO-205, and HT-29 [81]. GSK2194069 was identified from a high-throughput screen of the GSK compound collection, and this agent inhibits cell growth of A549 cells [82].
4.11. Conclusion of FASN inhibitors
Several studies have shown in vitro and in vivo anti-tumor activity of FASN inhibitors. This chapter shows that many FASN inhibitors are being examined for in vitro and in vivo anti-tumor activity of CRC. In addition, one of the FASN inhibitors, EGCG, has moved on to clinical trials aimed at preventing Colon polyp recurrence, which indicates the safety of monoterpenes for clinical use. Other FASN inhibitors are effective in in vitro/in vivo researches, and the clinical trials of using these reagents are expected, but still need more research. Newly developed agents, such as TVB-3166, TVB-3567, and GSK2194069, are expected to become new candidates for chemotherapeutic agents against unresectable cancers.
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