Supplements with Potential Efficacy But Not Yet Clinically Tested
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Supplements with Potential Efficacy But Not Yet Clinically Tested

  • Monday, 12 January 2009 10:20
  • Last Updated Friday, 12 October 2012 12:43

The following article is taken from 'Treatment Options for Glioblastoma and other Gliomas' prepared by Ben A. Williams

Glioblastoma Diagnosis, March, 1995
Last Updated: October 31, 2011

Copyright 2011, Ben Williams


Disclaimer: the information presented here is the opinion of Ben Williams. It is for informational purposes only, do not consider it medical advice. Discuss the ideas presented here with your own doctors.

Click on the links below to view details on each of the following supplements:

Genistein

Selenium

Green Tea

Quercetin

Curcumin

Silibinin (an ingredient of Silymarin)

Lycopene

Boswellic Acid

Broccoli Sprouts

Ellagic Acid

Berberine

Resveratrol

Garlic

 


 

Genistein

This is an isoflavone derived from soy products (it is also found in red clover extract) that has been shown in the laboratory to be highly cytotoxic to many different types of Cancer, including Glioma cells. In addition to the laboratory evidence, there is also substantial epidemiological evidence that high dietary intakes of soy products decrease cancer mortality by at approximately 50%. Only recently has it begun to be studied in clinical trials, mainly for prostate cancer, the results of which have been mixed.

Soy extracts containing genistein are available in most health-food stores. The concentration of genistein is often not well specified. Most importantly, the listed amounts of genistein are so low that they are unlikely to provide much clinical benefit. The highest concentration (about 10 times greater than the others that I have found) is made by the Life Extension Foundation (phone: 800-841-5433 begin_of_the_skype_highlighting              800-841-5433      end_of_the_skype_highlighting; website: lef.org). It can be ordered from them or from L&H Vitamins, a discount mail-order company that is a good source for many types of products otherwise found in health-food stores (phone #: 800-221-1152).

Although there is as of yet no strong evidence of the clinical effectiveness of genistein, the laboratory studies that are available make a strong case for its potential efficacy. In one representative laboratory experiment mice received different concentrations of genistein added to their regular diet (167). The measure of its effect was the number of lung Metastases caused by melanoma cells injected into the mice. The number of lung tumors was reduced by 50-75% depending upon the amount of genistein added to the diet. Interestingly, even greater inhibition of Tumor growth was observed in another study when whole soy extracts were added to the diet, rather than genistein alone (soy contains numerous isoflavones other than genistein).

Recent experimental studies have examined the mechanisms whereby genistein produces its anti-cancer effects (168). The consensus is that this results from its ability to inhibit tyrosine kinase activity. This is a general class of chemical signals that strongly stimulate cell division. The epidermal growth factor, discussed earlier with respect to the mechanism of accutane's effect, is one member of this class of signals, and some investigators believe that genistein works by blocking the EGF receptor. Genistein also appears to produce inhibition of protein kinase C (discussed earlier with respect to the mechanisms of tamoxifen. This in turn suggests that a combination of genistein and tamoxifen might be especially effective. Finally there is increasing evidence that genistein is an inhibitor of angiogenesis.

Of special interest to brain cancer patients is a recent laboratory study in which glioblastomas cells were treated with a combination of genistein and BCNU (169). The result was a highly synergistic suppression of the rate of growth. This observation is important because genistein has much in common with new drugs being developed to block the EGF signaling channel, which themselves seem to be more effective when used in combination with conventional treatment modalities.

167. Li, D., et al. Soybean isoflavones reduce experimental metastasis in mice. Journal of Nutrition, 1999, Vol. 129, pp. 1628-1635

168. Peterson, G. Evaluation of the biochemical targets of genistein in tumor cells. Journal of Nutrition, (1995), 125,S784-789

169. Khoshyomn, S., et al. Synergistic effect of genistein and BCNU in growth inhibition and cytotoxicity of glioblastoma cells. Journal of Neuro-oncology, 2002, Vol. 57, 193-210


Selenium

This is a trace element commonly found in the soil, which is absorbed into various foods, most commonly onions and garlic. Its potency as an anti-cancer agent was discovered almost by accident in a randomized placebo-controlled trial in which selenium was being tested as a possible preventative agent for skin cancer (170). While selenium had no effect on the incidence of skin cancer, it had substantial effects on the incidence of other types of cancer, including lung, colorectal, prostate, and the total of all cancers. The most dramatic effect occurred for prostate cancer, for which the incidence was reduced by 63% for those receiving selenium relative to the rate in the placebo controls. The incidence of brain cancer was not recorded in this study. An important question is whether selenium is effective as a treatment for existing cancers in addition to being useful as a cancer preventative. Laboratory research suggests that it should indeed be effective, as it has been shown to inhibit tumor growth in a dose-dependent manner in vitro, and its use as a dietary supplement significantly inhibits the growth of pulmonary metastases after injection of melanoma cells into mice (171). Laboratory studies also have shown it to inhibit the growth of glioma cells (172). Recent studies have identified two of its mechanisms of action, inhibition of protein kinase C (173), known to be important in the growth of gliomas, and inhibition of angiogenesis (174). It is important to note that selenium can be highly toxic at high dosages, and that the degree of toxicity varies with the compound in which it comes. Selenomethionine is the preferred form because it is the least toxic. The most common dosage used is 200 micrograms/day. There is some evidence that its effects may be synergistic with Vitamin D.

170. Clark, L. C. et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA, 1996, Vol. 276 (24), pp. 957-1963

171. Yan, L. et al. Dietary supplementation of selenomethionine reduces metastasis of melanoma cells in mice. Anticancer Research, 1999, Vol. 19 (2A), pp. 1337-1342

172. Sundaram, N., et al. Selenium causes growth inhibition and apoptosis in human brain tumor cell lines. Journal of Neuro-Oncology, 2000, Vol. 46, pp. 125-133

173. Gopalakrishna, R., & Gundimedia, U. Protein kinase C as a molecular target for cancer prevention by selenocompounds. Nutrition and Cancer, 2001, Vol. 40, 55-63

174. Lu, J., & Jiang, C., Antiangiogenic activity of selenium in cancer chemoprevention: metabolite-specific effects. Nutrition and Cancer, 2001, Vol. 40, 64-73


Green Tea

Green tea has been consumed in both China and Japan for 5000 years based on its medicinal properties A recent review has summarized its anti-cancer effects in several different animal models using both mice and rats (including major inhibition of glioblastoma cell lines), both when human tumors have been implanted and when they have been induced by various chemical carcinogens (175). In a representative study of chemically-induced tumors in mice (176), green tea was provided as the sole source of fluid, at a concentration of 6% (6 g of tea per liter of water), the incidence of lung tumors was reduced by 30%. The same study identified several different mechanisms of action, the most prominent of which was the inhibition of angiogenesis.

The major active ingredient in green tea is EGCG, one of a family of molecules known as catechins. Not only has this molecule been shown to be cytotoxic to glioma cells in vitro, but it also substantially increases the effectiveness of both cisplatin and tamoxifen (177). A recent review by the new Division of Alternative Medicine of the National Institutes of Health has identified green tea as the most promising of treatments advocated by proponents of alternative medicine. Accordingly, several clinical trials investigating its efficacy are ongoing. The only one reported to date used green tea in the treatment of patients with androgen independent metastatic prostate cancer (178). Dosage was 6 g of green tea per day. Only limited clinical benefit was reported. It is important to recognize that anti-angiogenic agents generally take a long time to produce clinical regressions, work better with less advanced stages of disease, and also work better in combination with other treatment agents.

175. Kuroda, Y. and Hara, Y. Antimutagenic and anticarcinogenic activity of tea polyphenols. Mutation Research, 1999, Vol. 436, pp. 69-97

176. Liao, J., et al. Inhibition of lung carcinogenesis and effects on angiogenesis and apoptosis in A/J mice by oral administration of green tea. Nutrition and Cancer, 2004, 48, 44-53

177. Shervington, A., et al. The sensitization of glioma cells to cisplatin and tamoxifen by the use of catechin. Mol. Biol. Rep., 2008, June 26 Epub ahead of print)

178. Jatoi, A., et al. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer, 2003, 97, 1442-1446

 


 

Quercetin

This is a member of the class of flavonoids found in fruits and related plant products. Its most abundant sources are onions, shallots, and apples. Like genistein it appears to be an inhibitor of tyrosine kinase activity, and appears to be synergistic with genistein when the two have been combined in laboratory studies involving both ovarian and breast cancer cell lines. It currently is being investigated in phase-1 clinical trials. Given that apples are one of its major sources, it is interesting that a story in Nature (June 22, 2000) has reported that material extracted from fresh apples inhibited in a dose-dependent manner the growth of both colon and liver cancer cell lines.


Curcumin

This is an ingredient in the Indian cooking spice, turmeric. It has been shown to inhibit the growth of cancer cells of various types in laboratory studies (179). Like genistein and quercetin, it inhibits the tyrosine kinase signaling and also inhibits angiogenesis. When the three supplements have been directly compared, curcumin was the more powerful inhibitor, but it also should be noted that its bioavailability from oral intake is limited. However, bioavailability supposedly is increased when curcumin is combined with piperine (the main ingredient in black pepper).

179. Aggarwal, B. B., et al. Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Research, 2003, Vol. 23, 363-398


Silibinin (an ingredient of Silymarin)

Silymarin is an extract from the milk thistle plant that has been used extensively in Europe as an antidote for liver toxicity, due to mushroom poisoning and overdoses of tylenol. Its active ingredient is a molecule called silibinin. Recently a great deal of laboratory research has shown it to have anti-cancer effects, which recently have been reviewed (180) Like genistein and quercetin it is a tyrosine kinase inhibitor, but it appears to have multiple other effects, including the inhibition of the insulin-like growth factor (IGF) that contributes to the development of chemoresistance (181) (see the section on tamoxifen), and the inhibition of angiogenesis (182). It also inhibits the 5-lipoxygenase inflammatory pathway and suppresses nuclear factor kappa B, which is known to be antagonistic to apoptosis (183) It also appears to protect against common Chemotherapy toxicities (184), while at the same time increasing the effectiveness of chemotherapy (185).

180. Ramasamy, K., and Agarwal, R., Multitargeted therapy of cancer by silymarin. Cancer Letters, 2008, May 8 (Epub ahead of print)

181. Singh, R. P., et al. Dietary feeding of silibinin inhibits advanced human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Research, 2002, Vol. 62, 3063-3069

182. Jiang, C., et al. Anti-angiogenic potential of a cancer chemopreventive flavonoid antioxidant, silymarin: inhibition of key attributes of vascular endothelial cells and angiogenic cytokine secretion by cancer epithelial cells. Biochemical and Biophysical Research Communications, 2000, Vol. 276, 371-378

183. Saller, R., et al. The use of silymarin in the treatment of liver diseases. Drugs, 2001, 61, 2035-2063

184. Bokemeyer, C., et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumor activity. British Journal of Cancer, 1996, Vol. 74, 2036-2041

185. Scambia, G., et al. Antiproliferative effect of silybinin on gynecological malignancies: synergism with cisplatin and doxorubicin. European Journal of Cancer, 1996, Vol. 32A, 877-882

 




Lycopene

 

This is a carotenoid that is found most abundantly in tomatoes but occurs in various other red-colored vegetables as well (including watermelon). Unlike the most well-known carotenoid, beta-carotene, it does not get transformed into Vitamin A, and thus has no hepatic toxicity. In a small clinical trial involving prostate cancer patients about to undergo surgery (186), for those who consumed lycopene for several weeks before surgery both the size and malignancy of their tumors were significantly reduced relative to those not receiving lycopene. Several other more recent studies have shown that lycopene as a single agent reduces PSA in prostrate cancer patients whose tumors have become hormone-independent. In an experimental study involving both cell cultures and implanted glioma tumors in rats (187), lycopene (and beta-carotene) were found to substantially inhibit tumor growth in both experimental preparations, and in fact had a greater inhibitory effect than did a collection of retinoids commonly used clinically. The only report of lycopene’s use with glioma patients is from a meeting abstract of a clinical trial in glioma patients that assessed the effect of adding 8 mg/day of lycopene to a protocol involving radiation + taxol (188) . Eighty percent of patients receiving lycopene had either complete or partial tumor regressions, while this was true for only 44% of those receiving a placebo. Of further relevance to gliomas is that one of lycopene's mechanisms of action is to inhibit the insulin-like growth factor, which as noted above is involved in the development of resistance to a variety of different treatment agents. (189). Also of interest is evidence that it synergizes with Vitamin D (190).

191. Safayhi, H. et al. Boswellic acids: novel, specific, nonredox inhibitors of 5- lipoxygenase. Journal of Pharmacology and Experimental Therapeutics, 1992, Vol. 261, 1143-1146'

192. Glaser, T., et al. Boswellic acids and Malignant glioma: induction of apoptosis but no modulation of drug sensitivity. British Journal of Cancer, 1999, Vol. 80, 756- 765

193. Winking, M., et al. Boswellic acids inhibit glioma growth: a new treatment option? Journal of Neuro-oncology, 2000, Vol. 46, 97-103

 




Boswellic Acid

 

This an extract from Indian folk medicine used for its anti-inflammatory effects. Laboratory studies have shown that its mechanism of action is inhibition of the lipoxygenase inflammatory pathway, which is the source of inflammatory leukotrienes(191). This inflammatory pathway is distinct from the cyclogenase pathway that was discussed earlier in the section on Celebrex and other NSAIDs. Boswellic acid is now used in Germany as a substitute for steroids as a method of reducing the Edema associated with gliomas. There have also been reports (192, 193) from in vivo animal laboratory experiments that it has direct anti-cancer effects . It seems plausible that its combination with celebrex or other COX-2 inhibitors might be synergistic.

191. Safayhi, H. et al. Boswellic acids: novel, specific, nonredox inhibitors of 5- lipoxygenase. Journal of Pharmacology and Experimental Therapeutics, 1992, Vol. 261, 1143-1146'

192. Glaser, T., et al. Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity. British Journal of Cancer, 1999, Vol. 80, 756- 765

193. Winking, M., et al. Boswellic acids inhibit glioma growth: a new treatment option? Journal of Neuro-oncology, 2000, Vol. 46, 97-103


Broccoli Sprouts

Brassica vegetables such as broccoli, cauliflower, brussel sprouts, and cabbage have long been believed to have anti-cancer properties, with the prevailing theory of the basis of that effect being that they contain a substance known as sulphoraphane. Recently it has been discovered that the 3-4 day-old sprouts of these vegetables contain 10-100 times the concentration of sulphoraphane as do the full-grown vegetables. To test whether the oral ingestion of sprouts has anti-cancer effects, dried broccoli sprouts were included in the diet of rats with chemically-induced cancers, with the result that considerable regression of the tumors were observed (194). Broccoli sprouts are also very tasty additions to salads.

194. Fahey, J. W., et al. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proceedings of the National Academy of Sciences, 1997, Vol. 94 (19), pp. 10367-10372


Ellagic Acid

This is a phenolic compound present in fruits and nuts, including raspberries, blueberries, strawberries, pomegranate juice, and walnuts. In laboratory experiments it has been shown to potently inhibit the growth of various chemical-induced cancers, with the basis of the effect being an arrest of cell division in the G stage of cell division, thus producing the programmed cell death known as apoptosis. While there have been no trials to assess its clinical effects with human patients, it should be obvious that quantities of berries and nuts are among the more enjoyable dietary components, and even the possibility that they may have anti-cancer effects should encourage their usage.

 




Berberine

This is an alkaloid extract from Coptides Rhizoma commonly used in China as an herbal medicine. It is also found in high concentration in the widely-used supplement, goldenseal. In one laboratory study of using both various kinds of glioma cell cultures and implanted tumors in rodents (195), the cytotoxic effects of berberine were compared to those of BCNU and to the combination of berberine and BCNU. Berberine alone produced a 91% kill rate in cell cultures, compared to 43% for BCNU. The combination produced a kill rate of 97%. Comparable results were obtained with the in vivo implanted tumors. Such results suggest that berberine is among the most promising treatment agents, but to date very little research using it has been reported. In part this opinion is based on the fact that the structure of berberine is closely related to Ukrain, a drug that combines an alkaloid from a plant named celandine combined with an old chemotherapy agent named thiotepa. After years of Ukrain’s use only in alternative medicine, it recently has been licensed for commercial development. A recent clinical trial using it for pancreatic cancer has produced very impressive results (196)

195. Zhang, R. X., et al. Laboratory studies of berberine used alone and in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea to treat malignant brain tumors. Chinese Medical Journal, 1990, 103, 658-665

 

196. Gansauge F, et al. The clinical efficacy of adjuvant systemic chemotherapy with gemcitabine and NSC-631570 in advanced pancreatic cancer. Hepatogastroenterology. 2007 Apr-May; 54(75): 917-20.


 

Resveratrol

This is a naturally occurring polyphenol found most abundantly in grapes and mulberries. Red wine is among the sources. Numerous experimental studies have shown that it inhibits proliferation of various kinds of cancer, including leukemia, prostate, breast, and colon cancer. Among its mechanisms of action are activation of the P53 gene, inhibition of protein kinase C, and the inhibition of new blood vessel growth. In the one recent study of its use with implanted glioma tumors (197), rats received either sub-cutaneous injections or intra-cerebral injections of tumor cells, which in control animals rapidly grew and became fatal. With sub-cutaneous tumors a dose of resveratrol of 40mg/kg produced major growth inhibition with 70% of the rats becoming long-term survivors. A higher dosage (100 mg/kg) was necessary to inhibit the growth of the Intracranial tumors, and even it was only marginally effective. The difference in outcome for the two preparations suggests that resveratrol may be impeded by the blood-brain barrier. However, the authors note that it had significant anti-angiogenic effects, which are not affected by the blood-brain barrier. Whether resveratrol has clinical utility for brain cancer is unclear, although it is known that anti-angiogenic agents of various sorts synergize with various kinds of conventional treatment.

197. Tseng, S. H. et al. Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clinical Cancer Research, 2004, 10, 2190-2202

 




Garlic

 

Garlic like green tea has been used hundreds of years for its medicinal purposes. A recent cell culture study with glioblastoma cell lines demonstrated its potent cytotoxic effects that were mediated by its ability to induce apoptosis (198).

198. Das, A., et al. Garlic compounds generate reactive oxygen species leading to activation of stress kinases and cysteine proteases for apoptosis in human glioblastoma T98G and U87MG cells.



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