Townsend’s New York Observer

by Marcus A. Cohen

Phytochemicals and Ovarian Cancer:

Preventive, Therapeutic, and Synergistic Benefits

As most people know by now, conventional treatment for cancer calls for whole or partial surgical removal of tumors when possible, and chemotherapy, radiation, or combined chemo/radiation for inoperable tumors. Chemo and radiation, especially systemic chemo, hit surrounding healthy tissue as well as the targeted malignant tissue, and leave adverse side effects. For decades, mainstream cancer specialists have sought means to reduce the severity of the “collateral” damage and side effects.

Phytochemicals

Recent mainstream research has taken hints, so to speak, from alternative or unconventional treatments (which largely use natural substances with minimal toxicity as therapy) and focused attention on phytochemicals. One can define phytochemicals as bioactive nonnutrient plant compounds. (Phyto comes from Attic Greek, and means “plant.”) Researchers have identified more than 5000 individual phytochemicals in fruits, vegetables, grains, and other plant foods. The chief dietary sources of phytochemicals include cruciferous vegetables, garlic, ginger, grapes, green tea, soybeans, and turmeric. Scientific evidence has linked many of these plant substances to reductions in the risk of developing severe chronic diseases.

Researchers have also amassed information on the cellular mechanisms by which phytochemicals, such as curcumin (a spice in curry) or epigallocatechin gallate (extracted from tea), interfere with disease progression. This information has revealed, too, that phytochemicals boost the anti-inflammatory defense system in humans, and sensitize malignant cells to cytotoxic agents.

In cancer, these natural compounds have been shown to target multiple signaling pathways involved in the development of malignancies, such as angiogenesis, apoptosis, and cell proliferation. Given the complex “crosstalk” between cell signaling pathways in individual cancers, phytochemicals that affect diverse pathways have an advantage over targeting-agents; the latter inhibit single pathways, modestly inhibiting tumor growth.

Ovarian Cancer

The fifth leading cause of cancer deaths in women, ovarian cancer is the deadliest gynecologic malignancy. The National Cancer Institute (NCI) estimates that there will be 21,900 new cases of ovarian cancer in the US in 2011, and 15,460 deaths.

The poor prognosis of ovarian cancer results mainly from the high percentage of cases diagnosed at an advanced stage. (Often, there are no symptoms in the early stages.) Most patients with advanced ovarian cancer respond to first-line chemotherapy, but ultimately 80% will suffer a recurrence and die.

More than 90% of ovarian cancers are epithelial in origin and are thought to arise from ovarian surface epithelium or inclusion cysts. Multiple genetic alterations are implicated in ovarian carcinogenesis, but there are multiple lines of clinical and genetic evidence to support two broad categories of ovarian carcinogenesis; those of low-grade and high-grade pathways.

Recently, however, another compelling hypothesis has highlighted the role of inflammation in ovarian cancer. Inflammation, it has been suggested, is involved all steps in carcinogenesis, including tumor initiation, promotion, and progression. Components of the inflammatory pathway include free radicals, cytokines, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandins, and vascular endothelial growth factor (VEGF). Studies point to these factors (and several others) as contributors in the development of various malignancies, including ovarian cancer.

The ovulation process itself is believed to be associated with inflammatory pathways. Ovarian surface epithelium adjacent to the site of ovulation may be exposed to inflammatory cytokines and prostaglandins and may undergo active replication, thereby enhancing the risk of malignant transformation. In addition, there is epidemiologic evidence supporting the role of inflammation in ovarian carcinogenesis.

Dietary Flavonoids as Preventives

New research suggests that diets high in certain flavonoid compounds may significantly lower a woman’s risk of developing ovarian cancer. Flavonoids are a large family of antioxidant compounds found in vegetables, fruits, beans, and tea. They are part of a plant’s natural defense system helping the plant fight off disease and infection.

This new research provides evidence that favonoids ward off various diseases in humans by protecting cells from DNA damage. Scientists believe some flavonoids may also deter cancer development by helping to regulate cell growth or by changing hormone levels. A new study, published in the International Journal of Cancer in 2007, involving almost 67,000 women in the Nurses’ Health Study, looked at flavonoid consumption over 14 years. Total flavonoid consumption appeared unrelated to the risk of developing ovarian cancer. But two particular flavonoids were related.

Kaempferol

(present in tea, broccoli, kale and spinach) and

luteolin

(present in peppers, carrots, cabbage and celery), were both identified as protective. Women who consumed the greatest amount of these two flavonoids were 40 percent and 34 percent less likely (respectively) to develop ovarian cancer, compared to women who consumed the least. Women consuming high levels of a third phytochemical,

myricetin

(present in tea, dried beans, raisins and blueberries), also seemed somewhat protected.

Another landmark report on diet and cancer risk, published by the American Institute for Cancer Research in 2007, noted some evidence suggesting that non-starchy vegetables may offer protection against ovarian cancer. The report emphasizes that protection could come from any of several families of phytochemicals, as well as dietary fiber, vitamins, and minerals. The researchers advised that determining the relative importance of one individual constituent in a given food is hard, and that a protective effect most likely comes from a combination of influences on several pathways involved in carcinogenesis.

Evidence that supports the preventive role of phytochemicals in ovarian cancer continues to grow. A 2007 study published in the British Journal of Nutrition linked greater consumption of carotenoid phytochemicals with a 67 percent lower risk of ovarian cancer. This included not only

beta-carotene

(in deep-orange vegetables and fruits), but also

alpha-carotene, beta-cryptoxanthin, lutein

and

zeaxanthin

— carotenoids found in a broad range of green, orange, red, and yellow vegetables. This study reinforced an earlier study, which found a reduction in ovarian cancer risk of greater than 50 percent among women whose diet was rich in vegetables.

Other Beneficial Phytochemicals, Some with Therapeutic Effects

A component of the spice turmeric,

curcumin

has traditionally been used as an anti-inflammatory agent. Recent studies have demonstrated that curcumin has antioxidant, anti-proliferative, and antiangiogenic activities through interaction with multiple signaling pathways In one study, treatment with curcumin alone or in combination with docetaxel increased tumor cell apoptosis in multidrug-resistant ovarian cancer tumors.

A soy-derived isoflavone,

genistein

has shown protective effects against endocrine-related gynecological cancers. (Increased soy consumption appears to decrease the risk of ovarian cancer.) Additionally, genistein has been shown to inhibit cell proliferation and induce apoptosis in ovarian cancer cells. Genistein treatment also induces autophagic cell death in ovarian cancer cells

Epigallocatechin-3-gallate (

EGCG

), a polyphenol in green tea, has shown anti-proliferative and pro-apoptotic effects on several kinds of cancers. In several ovarian cancer cell lines, EGCG exerted an inhibitory effect on cancer cell growth through the induction of apoptosis and cell cycle arrest as well as the regulation of cell cycle-related proteins.

Resveratrol

, a phytoalexin abundant in grape skins and red wine, has been shown to inhibit proliferation and induce apoptosis in various cancer cell lines, including breast, prostate, colon, and ovarian cancer cells. In nude mice implanted with human ovarian cancer cells, resveratrol suppressed tumor growth when it was administered intraperitoneally. Resveratrol also enhanced the effectiveness of the chemotherapeutic agents cisplatin and doxorubicin in ovarian cancer cells, while reducing doxorubicin-related cardiac toxicity. The inhibitory effects of resveratrol on tumor growth have been attributed in part to this phytochemical’s anti-inflammatory activity.

Synergistic Effects

A major cause of treatment failure in cancer is resistance by malignant cells to chemotherapy. From in vitro tissue culture and in vivo xenograft studies with drug-resistant human cancer cell lines, synergistic effects have been shown between chemotherapy and phytochemicals.

Shen F et al (published 1997) tested genistein and quercetin (a flavonoid found in fruits, vegetables, leaves, and grains) to determine whether these two phytochemicals might be synergistic in ovarian cancer.¹ The chemo of choice in ovarian cancer is cisplatin, but patients who become resistant to cisplatin respond poorly to other available chemotherapeutic agents; so Shen et al felt it vital to discover novel targets for ovarian cancer. When the researchers added quercetin to cultures of OVCAR-5 cells, then added genistein eight hours afterward, they observed synergism in inhibition of cancer cell growth.

Raj MH et al (published 2008) analyzed the mechanism of action of two phytochemicals, resveratrol (RE) and Indole-3 Carbinol (I3C) when used alone and in combination in SK-OV-3 ovarian cancer cells.² According to this study’s abstract, both resveratrol and I3C are known anti-proliferative agents in cancer, and both show similar as well as unique molecular targeting profiles. (I3C is obtainable in relatively high amounts from cruciferous vegetables; bok choy, broccoli, cabbage, cauliflower, cress, and similar green leaf vegetables.)

The investigators reported complex results. RE or I3C caused apoptosis and cell contraction, and cell proliferation. The “Results” section of the abstract noted a synergistic action of I3C combined with RE in thwarting cancer cell proliferation. Theirs was the first study, said the investigators, “demonstrating the effects of I3Cy on ovarian cancer cells and its synergism with RE.”

Yunos NM et al (published 2011) studied synergistic activity from the sequenced combinations of cisplatin with curcumin and EGCG in human ovarian cancer cell lines. ³ When sequenced combinations of cisplatin with curcumin and with EGCG are applied to certain human ovarian cancers, the investigators noted that“lower concentrations and shorter time gap between the two additions seem to produce a higher cytotoxic effect” (meaning, importantly, more tumor kill in less time).

I’d like to project a time (in the intermediate future) when mainstream research on phytochemicals will end with the natural substances replacing pharmaceutical drugs in cancer prevention and even treatment. It’s a rational progression. It’s good science, too. It would let us say “bye-bye” at last to severe adverse effects of chemo!

But Western mainstream medicine is mostly profit-primed, so researchers testing phytochemicals on human cancer in labs (comparatively cheap and quick) can probably count on more and more funding, while not even a glut of promising results from cell line and animal studies is likely to advance phytochemicals to human clinical trials.

I thought it proper to cite the articles in the synergism section of this column. In the rest of this column, I’ve drawn information from more general articles on phytochemicals and listed these articles under “References.”

Notes

1. Shen F et al. Synergistic action of quercetin and genistein in human ovarian carcinoma cells.

1997;9(11–12):597–602.

2. Raj MH et al. Synergistic action of dietary phyto-antioxidants on survival and proliferation of

ovarian cancer cells. Gynecol Oncol. 2008 Sep;110(3):432–438

3. Yunos NM et al. Synergism from sequenced combinations of curcumin and epigallocatechin 3-

gallate with cisplatin in the killing of human ovarian cancer cells. Anticancer Res. 2011

Apr;31(4):1131–1140.

References

Kim M-K et al. Modulation of inflammatory signaling pathways by phytochemicals in ovarian

cancer. Genes Nutr. 2011 May;6(2):109–115.

Chan MM et al. Overcoming drug resistance by phytochemicals. Drug Resistance in Cancer Cells.

2009;315–342.

Liu RH. Potential synergy of phytochemicals in cancer prevention: mechanism of action. J. Nutr

December 1, 2004;134(12)3479S–3485S.

Marcus A. Cohen’s “baptism” in the whirlpools of medical politics dates to 1984, when he served as government and media liaison for patients under alternative cancer therapy. Subsequently, he has advocated broadening plausible treatment options for patients unresponsive to conventional care. A Townsend Letter columnist since 2004, he has reported and commented on a wide range of health-care topics; he is also the author of a paperback, Lyme Disease Update, published by the Lyme Disease Association in 2004.