Phytochemicals in the treatment of ovarian cancer
Ovarian cancer ranks 5th among the most common gynecologic cancers and causes the highest mortality in females. Here, we discuss the role of a group of natural products that are being used in treatment and prevention of a host of cancers including ovarian cancer. Some plants and nutraceuticals and their polyphenolic constituents such as flavones, flavonoids, and antioxidants have shown cytotoxic effects on cancer cells both in vitro and in vivo. While phytochemicals do not harm normal cells, they have been found to be cytotoxic to cancer cells by virtue of inhibition of proliferation and/or induction of apoptosis, making them ideal in cancer therapeutics or as adjunct to conventional treatment regimens.
Ovarian cancer is the most common and 5th most lethal malignant neoplasm of female reproductive tract (1). Such a high rate of death is due to late detection with diagnosed cases being in the late stage of the disease due to lack of symptoms and detectable biomarkers (2). According to World Health Organization, ovarian cancer is characterized as a heterogeneous group of diseases which includes serous, mucinous, clear cell, squamous and endometrioid carcinoma (3, 4). The distinct molecular and genetic profiles of these cancer types and their varied response to treatment makes it difficult to design a common therapeutic regimen (3). The tumor microenvironment of ovarian carcinoma is comprised of fibroblasts, immune cells, and endothelial cells of the host as well as non-cellular components including the extracellular matrix (ECM), ECM remodeling enzymes [e.g., matrix metalloproteinases (MMPs), tissue inhibitors of metalloprotein-ases (TIMPs), and lysyl oxidases (LOXs)], and growth factors (e.g., VEGF, TGF-β, and PDGF). This microenvironment is permissive to tumor cell growth, migration, and invasion. Despite the advances in therapies available for initial staged ovarian carcinoma patients, So far, treatment of ovarian cancers that are diagnosed in the early stage of the disease only modestly increased survival rate (5). The survival is even lower in carcinomas that are diagnosed at late stage of disease with cytoreductive surgery and combination therapy being the only available treatment (6). Awide spectrum of cytokines, growth factors, adhesion molecules, proteases, hormones, coagulation factors, acute phase reactants, apoptotic factors have been investigated in search of effective cancer treatment.
The history of therapeutic use of plants can be traced back to the Sumerian and Akkadian civilizations. Extensive in vitro and in vivo studies have shown that phytochemicals with bioactive properties including neutraceuticals and their polyphenolic constituents such as flavones, flavonoids, antioxidants etc provide considerable protection against many cancer types (Table 1). Anumber of studies have also revealed also have shown a geat potential of phytochemicals in enhancing the effects of conventional therapy or used alone for treating several types of cancer (7). Some phytochemicals influence multiple targets through a common oncogenic signaling pathway (8).
|Dietary Supplements||Latin Name||Potential Active Components||Major Potential Health Benefit|
|Astragalus||Astragalus membranaceus||Polysaccharides, saponins(astragalosides)||Immunomodulatory, hepatoprotective|
|Black cohosh||Cimicifuga racemosa||Fukinolic acid||Relief of menopausal symptoms|
|Cranberry||Vaccinium macrocarpon||Proanthocyanidins||Prevention and treatment of urinary tract infections|
|Dang Gui||Angelica sinensis||Ligustilide||Treatment of gynecological conditions|
|Echinacea||Echinacea purpurea, E. pallida, E. angustifolia||Polysaccharides and glycoproteins, cichoric acid, Alkamides||Treatment of common cold, cough, and upper respiratory infections|
|Feverfew||Tanacetum parthenium||Parthenolide and other sesquiterpene lactones||Alleviation of fever, headache, and women’s ailments|
|Garlic||Allium sativum||Allyl sulfur compounds||Antibacterial, anticarcinogenic, antithrombotic, hypolipidemic|
|Ginger||Zingiber officinale Roscoe||Gingerols||Antiemetic, anti-inflammatory, digestive aid|
|Ginkgo biloba||Ginkgo biloba||Ginkgolids, flavonoids||Treatment of cerebral dysfunction and circulatory disorders|
|American ginseng||Panax quinquefolium||Ginsenosides||Therapeutic effects on immune function, cardiovascular diseases, cancer, sexual function|
|Asian ginseng||Panax ginseng||Ginsenosides||Combat psychophysical tiredness and asthenia|
|Goldenseal||Hydrastis canadensis||Alakaloid berberine and β-hydrastine||Soothing irritated skin and mucous membranes, easing dyspepsia|
|Grape seed extract||Vitis vinifera||Proanthocyanidins||Antioxidant, anti-inflammatory, immunostimulatory, antiviral, and Anticancer|
|Green tea polyphenols||Camellia sinensis||Epigallocatechin gallate and catechins||Preventive effects on heart diseases, cancer, neurodegenerative disorders, and diabetes|
|Kava||Piper methysticum||Kava lactones||Effects on relaxing and mood calming|
|Licorice||Glycyrrhiza glabra||Triterpene saponins, flavonoids and other phenolics||Possess soothing, anti-inflammatory, and antitussive properties|
|Maca||Lepidium meyenii||Aromatic isothiocyanates||Use for aphrodisiac purpose|
|Milk thistle||Silybum marianum||Silymarin||Treatment of liver disorders|
|Pycnogenol||Pinus pinaster ssp. Atlantica||Procyanidins||Use for protection of circulation, and to restore capillary healing|
|Red clover||Trifolium pratense||Isoflavones||Treatment for menopausal symptoms|
|Reishi mushroom||Ganoderma lucidum||Triterpenoids, polysaccharides||Antitumor and immunomodulating effects|
|Saw Palmetto||Serenoa repens||Unknown||Use for prostate health|
|Soy isoflavones||Glycine max||Genistein, daidzein||Prevention of menopausal symptoms, osteoporosis, coronary heart disease, and cancer|
|St John’s wort||Hypericum perforatum||HyperfoWrin, hypercin||Treatment of mild depression|
|Valerian||Valeriana officinalis L.||Valepotriates(iridoids)||Use for mild sedative and sleep disturbance|
|Yohimbe||Pausinystalia johimbe||Yohimbine||Use for aphrodisiac purpose|
3. Classification of phytochemicals
Many phytochemicals derived from fruits and vegetables have shown health promoting properties. These phytochemicals can be classified as terpenes, carotenoids, monoterpenes including perillyl alcohol and limonene, Saponins, phenols (polyphenols and flavonoids), organo-sulphur compounds (indoles, isothiocyanates and thiosulfonates), organic acid and polysaccharides (organic acids, polysaccharides), lipids (isoprenoids and omega-3 and omega-6 fatty acid).
Terpenes, the most widespread class of phytochemicals, contain flammable unsaturated hydrocarbons and exist mainly in a liquid form (9). They have general formula (C5H8)n and depending upon the carbon number they are classified as mono-, di-, tri-and sesquiterpenoids. The 3 major classes of terpenes are shown in Figure 1.
Carotenoids are natural fat soluble pigments which provide bright coloration to plants. A40-carbon polyene chain, which is derived from isoprene, forms the backbone of carotenoids. The polyene backbone consists of conjugated double bonds which allow the carotenoids to take up excess energy from other molecules through a non radiative energy transfer mechanism (10). These characteristics make carotenoids an efficient antioxidant compound. Carotenoids scavenge reactive oxygen and free radicals and their antioxidative properties enhance immune function, protect from sunburn and inhibit the development of certain types of cancers (11).
Source: Apricots, carrot, pumpkins and sweet potato are sources of β–carotene. Tomatoes and watermelon are sources of lycopene. Mango, papaya, peaches, prunes, oranges are the sources of lutein and zeaxanthin (12).
Mechanism of action: Mechanism of action of carotenoids remains uncertain but possibilities include antioxidative property, modulation of lipoxygenase activity, activition of certain gene responsible cell to cell communication and provitamin A activity (12).
Monoterpenes include perillyl alcohol and limonene (13).
220.127.116.11. Perillyl alcohol
Source: Essential oils of lavandin, peppermint, spearmint cherries, celery seeds and several other plants (14).
Mechanism of action: Perillyl alcohol is active in inducing apoptosis in tumour cells without affecting normal cells and can cause the tumor cells to differentiate. Perillyl alcohol increases mannose-6-phosphate, induces phase 1 and phase 2 detoxification system and decreases ubiquinone synthesis (14).
Limonene is a colorless liquid hydrocarbon classified as cyclic terpenes. Limonene possesses a strong smell of orange (15).
Source: Mandarins, oranges (15).
Mechanism of action: Limonene induces apoptosis and has anti-proliferative activity (15).
Saponins are derived from Saponaria Vaccaria ( Quillaja saponaria). Saponins are comprised of a Sugar (glycone) backbone plus sapogenin (aglycone). Saponins have a high molecular weight as they possess sugar molecule combined with triterpene or steroid aglycone. Saponins are usually soluble in water and insoluble in ether and are hydrolyzed to aglycone also known as sapogenin. Saponin glycosides are divided into two types based on the chemical structure of their aglycones (sapogenins) (16).
Source: Legumes, soybeans (16).
Mechanism of action: Saponins lower cholesterol, and have anti-cancer and immune stimulatory properties. Anti-cancer properties of saponins appear to be the result of antioxidative effect, immune modulation and regulation of cell proliferation (16).
Phenols are one of the largest families of phytonutrients with over 2000 members. They are responsible for the colour of fruits and plants and are mostly synthesized from phenylalanine by the action of phenylalanine ammonia lyase (PAL) (17). The simplest compounds have single phenolic units which is abundant in culinary herbs. Phenols are antioxidants with antimicrobial including antifungals property. They are broadly classified as shown in Figure 1 to polyphenols and flavonoids.
In fruits, vegetables and spices the existence of polyphenolic compounds are well marked. High dietary intake of polyphenols is associated with decreased cardiovascular disease, specific forms of cancer and neurodegenerative diseases (18).
Source: Tea, Red wine, Cocoa, fruit juices and olive oil (18).
Mechanism of action: Polyphenols involve two main mechanism of action:
a) Mechanism-I (modulation of enzymatic activity) (19).
b) Mechanism-II (modulation of cancer cell signaling) (19).
Flavonoids are synthesized in almost all plant tissues and there are at least 2000 naturally occurring flavonoids. They are grouped into seven classes: flavones, flavanones, flavonols, flavanonols, isoflavones, flavanols (catechins) and anthocyanidins (20).
Source: Edible fruits, leafy vegetables, roots, tubers, bulbs, herbs, spices, legumes, tea, coffee, and red wine (20).
Mechanism of action: Flavonoids have multiple effects on cells including (a) antioxidative property, (b)ability to scavenge active oxygen species and electrophiles, (c) inhibition of nitrosation, (d) ability to chelate metals (such as Fe and Cu), (e) producing hydrogen peroxide in presence of certain metals and (f) the ability to modulate certain cellular enzyme activities (20).
3.3. Organosulphur compounds
Phytonutrients of this family possess various forms of sulfur, which give them their characteristic pungent aroma. The sulfur compounds in the following two groups (Figure 1) are slightly different and consequently each has specific health benefits (21).
3.3.1. Indoles and isothiocyanates
Indoles and Isothiocyanates are formed during the mastication of some cruciferous vegetables (22).
Source: Indoles and Isothiocyanates are released from mustard greens and seeds, horse-raddish, cabbage (a rich source of indole-3-carbinol), broccoli, and cauliflower (22).
Mechanism of action: Indole-3-carbinol is a bioactive compound and induces and activates cytochrome P450 (Phase I enzyme) and glutathione S-transferase (Phase II enzyme) and this accounts for the cancer-preventive properties exhibited by this class of compounds (21). These compounds bind to chemical carcinogens and also activate liver detoxification enzymes that generate products with anti cancer properties (21).
This group of phytonutrients generally contains sulphur (23).
Source: Garlic and onion (23).
Mechanism of action: Crushing the plants containing thiosulfonates leads to the release of sulfur compounds such as allicin, allyl sulfides, allyl mercaptocystein with strong antioxidative properties. Specific allyl sulfides block the activity of toxins produced by bacteria and viruses (23) Garlic has anti-microbial properties and inhibits a large number of bacteria such as Helicobacter pylori. Garlic has also been shown to increase immunity and to prevent the stomach cancer (23).
3.4. Organic acid and polysaccharides
Many of the phytonutrients are rich in organic acids and polysaccharides (Figure 1).
3.4.1. Organic acids
Source: Oxalic acid (Tea, coffee, spinach), cinnamic acid (Aloe vera), ferulic (Oats, rice), gallic (tea), ellagic (guava), salicylic acid (peppermint) (24).
Mechanism of action: Organic acids have antioxidant, cancer preventive, liver protective effect and act as inflammatory mediators (24).
Source: Mushrooms (25).
Mechanism of action: Polysaccharides have anti-cancer effects and boost the immune system (25).
Phytochemical lipid includes unsaturated fatty acids, oils, fat-soluble vitamins, and fatty acid esters. The group includes isoprenoids that includes multiple 5-carbon isoprene units and a long unsaturated side chain, omega-3 and omega-6-fatty acids (Figure 1).
Isoprenoids consists of multiple 5-carbon isoprene units (26).
Source: Grains and palm oils (26).
Mechanism of action: Isoprenoids protect the phospholipid bi-layers in cell membranes from free radical damage. It also facilitates receptor function thus boosting the antioxidative power of individual cycle participants (26).
3.5.2. Omega-3 and omega-6 fatty acid
Source: Dark green leafy vegetables, grains, legumes, nuts and seeds. ALA-Seed oil such as primrose, borage. EPA and DHA found in fish, especially salmon, herring, tuna and white fish (27).
Mechanism of action: Omega-3 and omega-6 fatty acid reduce inflammation, platelet aggregation and immune response. These activities protect against cardiovascular diseases, cancer and many other forms of chronic diseases. DHA reduces depression, attention deficits and anxiety and prevents breast, prostate and colon cancer (27).
4. Mode of action of phytochemicals against ovarian cancer
Ovarian carcinoma is the 5thmost common and lethal gynecological cancer which causes deaths of approximately 60% of women who suffer from the disease. The mortality rate of this cancer has not changed significantly over the last three decades. Ovarian cancer cells have the tendency to develop resistance to conventional cancer treatments. Tumor growth is influenced and is enhanced by a microenvironment contributed by the host including endothelial cells, fibroblasts, and infiltrating inflammatory cells. These cells are recruited to the tumor microenvironment by cytokines and growth factors that are released by cancer cells (29). The type-1 and type-2 Epithelial Ovarian Cancer (EOC) cells release different cytokines including tumor necrosis factor-α (TNF-α) and IL-6 (29-36).
Phytochemicals including apigenin, baicalein, curcumin, genistein, luteolin, oridonin, quercetin, and wogonin have shown to deactivate NF-κB, a master switch in the inflammatory process within the tumor microenvironment either by preventing NF-κB nuclear transportation or by suppressing NF-κB protein activity (37-42).
One of the major challenges in the treatment of advanced EOC has been the development of resistance to treatment. Cancer cells can acquire drug-resistance by several mechanisms including mutation or deletion of the transcription factor TP53 which normally activates DNA repair and initiate apoptosis and loss of TRAIL-induced apoptosis (43). NF-κB and p53, have an antagonistic relationship in cancer (43-46). It has been shown that the tumor suppressor activity of p53 is reduced by the activation of NF-κB, thereby leading to conditions conducive to a dominant ontogeny mediated transformation. Many in vitro studies show upregulation of wild-type p53 protein in ovarian cancer by baicalein, curcumin, genistein, luteolin, quercetin, oridonin, resveratrol, and wogonin (47-50). TRAIL-resistant cancer cells were found to undergo apoptosis by baicalein, curcumin, luteolin, procyanidins, quercetin, resveratrol, sulphoraphane and wogonin (51-56). In human EOC cells, hispidulin potentiated the TRAIL-induced apoptosis (57).
Type2 aggressive EOC cells exhibit activated expression of VEGF and a high rate of vasculogenesis (58,59). Phytochemicals have shown promising effect by virtue of their effects on VEGF (60-62). 5 flavonoids including apigenin, luteolin, quercetin, genistein, and kaempferol have reduced in a dose dependent manner the cell growth and VEGF production in varian cancer cell line OVCAR-3 (63). Several studies have shown that wogonin and kaempferol inhibit VEGF protein expression in various cancer cells (64-66).
7. SC Thomasset, DP Berry, G Garcea, T Marczylo, WP Steward, AJ Gescher: Dietary polyphenolic phytochemicals—promising cancer chemopreventive agents in humans? A review of their clinical properties. Int. J. Cancer, 120, 451-458 (2007)
13. PL Crowell, AS Ayoubi, YD Burke: Antitumorigenic effects of limonene and perillyl alcohol against pancreatic and breast cancer. In Dietary Phytochemicals in Cancer Prevention and Treatment. Springer US 131-136 (1996)
17. C Omojate Godstime, O Enwa Felix, O Jewo Augustina, O Eze Christopher: Mechanisms of antimicrobial actions of phytochemicals against enteric pathogens–a review. J Pharm Chem Biol Sci 2, 77-85 (2014)
20. MT Huang, T Ferraro: Phenolic compounds in food and cancer prevention. In Phenolic Compounds in Food and Their Effects on Health II: Antioxidants & Cancer Prevention, ACS Symposium Ser. 507, American Chemical Society, Washington,D.C., 8–34 (1992).
27. CH MacLean, SJ Newberry, WA Mojica, P Khanna, AM Issa, MJ Suttorp, YW Lim, SB Traina, L Hilton, R Garland, SC Morton: (2006-01-25). ”Effects of omega-3 fatty acids on cancer risk: a systematic review.” JAMA 295, 403–15 (2006)
29. H Kulbe, R Thompson, JL Wilson, S Robinson, T Hagemann, R Fatah, D Gould, A Ayhan, F Balkwill: The inflammatory cytokine tumor necrosis factor-alpha generates an autocrine tumor-promoting network in epithelial ovarian cancer cells. Cancer Res. 67, 585-592 (2007)
30. AB Alvero, MK Montagna, V Craveiro, L Liu, G Mor: Distinct subpopulations of epithelial ovarian cancer cells can differentially induce macrophages and T regulatory cells toward a protumor phenotype. Am J Reprod Immunol, (2011)
31. H Kulbe, T Hagemann, PW Szlosarek, FR Balkwill, JL Wilson: The inflammatory cytokine tumor necrosis factor-alpha regulates chemokine receptor expression on ovarian cancer cells. Cancer Res 65, 10355-10362 (2005).
32. PP Szotek, R Pieretti-Vanmarcke, PT Masiakos, DM Dinulescu, D Connolly, R Foster, D Dombkowski, F Preffer, DT MacLaughlin, PK Donahoe: Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness. Proc Natl Acad Sci USA 103, 11154-11159 (2006)
33. J Coward, H Kulbe, P Chakravarty, D Leader, V Vassileva, DA Leinster, R Thompson, T Schioppa, J Nemeth, J Vermeulen, N Singh, N Avril, J Cummings, E Rexhepaj, K Jirstrom, WM Gallagher, DJ Brennan, IA McNeish, FR Balkwill: Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res 17, 6083-6096 (2011)
35. CM Annunziata, HT Stavnes, L Kleinberg, A Berner, LF Hernandez, MJ Birrer, SM Steinberg, B Davidson, EC Kohn: Nuclear factor kappaB transcription factors are coexpressed and convey a poor outcome in ovarian cancer. Cancer 116, 3276-3284 (2010)
36. G Kruppa, B Thoma, T Machleidt, K Wiegmann, M Kronke: Inhibition of tumor necrosis factor (TNF)-mediated NF-kappa B activation by selective blockade of the human 55-kDa TNF receptor. J Immunol 148, 3152-3157 (1992)
38. A Gulcubuk, K Altunatmaz, K Sonmez, D Haktanir-Yatkin, H Uzun, A Gurel, S Aydin, S: Effects of curcumin on tumour necrosis factor-alpha and interleukin-6 in the late phase of experimental acute pancreatitis. J Vet Med A Physiol Pathol Clin Med 53, 49-54 (2006)
39. NY Tang, JS Yang, YH Chang, HF Lu, TC Hsia, WC Lin, JG Chung: Effects of wogonin on the levels of cytokines and functions of leukocytes associated with NF-kappa B expression in Sprague-Dawley rats. In vivo 20, 527-532 (2006)
40. S Ahmed, H Marotte, K Kwan, JH Ruth, PL Campbell, BJ Rabquer, A Pakozdi, AE Koch: Epigallocatechin-3-gallate inhibits IL-6 synthesis and suppresses transsignaling by enhancing soluble gp130 production. Proc Natl Acad Sci U S A 105, 14692-14697 (2008)
41. Y Xu, Y Xue, Y Wang, D Feng, S Lin, L Xu: Multiple-modulation effects of Oridonin on the production of proinflammatory cytokines and neurotrophic factors in LPS-activated microglia. Int Immunopharmacol 9, 360-365 (2009)
42. JH Seo, KJ Jeong, WJ Oh, HJ Sul, JS Sohn, YK Kim, Y Cho do, JK Kang, CG Park, HY Lee: Lysophosphatidic acid induces STAT3 phosphorylation and ovarian cancer cell motility: their inhibition by curcumin. Cancer Lett 288, 50-56 (2010)
44. A Ventura, DG Kirsch, ME Mclaughlin, DA Tuveson, J Grimm, L Lintault, J Newman, EE Reczek, R Weissleder, T Jacks: Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661-665 (2007)
47. S Chen, Q Ruan, E Bedner, A Deptala, X Wang, TC Hsieh, F Traganos, Z Darzynkiewicz: Effects of the flavonoid baicalin and its metabolite baicalein on androgen receptor expression, cell cycle progression and apoptosis of prostate cancer cell lines. Cell Proliferat 34, 293-304 (2001)
48. S Chen: Natural products triggering biological targets — a review of the anti-inflammatory phytochemicals targeting the arachidonic acid pathway in allergy asthma and rheumatoid arthritis. Curr Drug Targets 12, 288-301 (2011)
49. R Shi, Q Huang, X Zhu,YB Ong, B Zhao, J Lu, CN Ong, HM Shen: Luteolin sensitizes the anticancer effect of cisplatin via c- Jun NH2-terminal kinase-mediated p53 phosphorylation and stabilization. Mol Cancer Ther 6, 1338-1347, (2007)
52. EM Jung, JH Lim, TJ Lee, JW Park, KS Choi, TK Kwon: Curcumin sensitizes tumor necrosis factor-related apoptosisinducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis 26, 1905-1913(2005)
53. ME Maldonado-Celis, S Bousserouel, F Gosse, A Lobstein, F Raul: Apple procyanidins activate apoptotic signaling pathway in human colon adenocarcinoma cells by a lipid-raft independent mechanism. Biochem Biophys Res Commun 388, 372-376 (2009)
56. DH Lee, JG Rhee, YJ Lee: Reactive oxygen species up-regulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin. Br J Pharmacol 157, 1189-1202 (2009)
58. JM Yang, CM Hung, CN Fu, JC Lee, CH Huang, MH Yang, CL Lin, JY Kao, TD Way: Hispidulin sensitizes human ovarian cancer cells to TRAIL-induced apoptosis by AMPK activation leading to Mcl-1 block in translation. J Agric Food Chem 58, 10020-10026 (2010)
59. RJ Kurman, K Visvanathan, R Roden, TC Wu, IM Shih: Early detection and treatment of ovarian cancer: shifting from early stage to minimal volume of disease based on a new model of carcinogenesis. Am J Obstet Gynecol 198, 351-356 (2008)
62. SY Park, KJ Jeong, J Lee, DS Yoon, WS Choi, YK Kim, JW Han, YM Kim, BK Kim, HY Lee: Hypoxia enhances LPAinduced HIF-1alpha and VEGF expression: their inhibition by resveratrol. Cancer Lett 258, 63-69 (2007)
65. H Luo, MK Daddysman, GO Rankin, BH Jiang, YC Chen: Kaempferol enhances cisplatin’s effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc. Cancer Cell Int 10, 16 (2010)
66. BH Zhu, HY Chen, WH Zhan, CY Wang, SR Cai, Z Wang, CH Zhang, YL He: (-)-Epigallocatechin-3-gallate inhibits VEGF expression induced by IL-6 via Stat3 in gastric cancer. World J Gastroenterol 17, 2315-2325 (2011)