Over-the-Counter Drugs and Supplements to Fight Glioblastoma (Part Two)
Here we are at the tenth episode of the Ben Williams guide translation project on treatment options for Glioblastoma Multiforme. This is the second part of chapter 7 of the guide which I have divided into two parts. In this second part we talk about Curcumin, Ellagic Acid, Fish Oil, Garlic, Genistein, Green Tea, Lycopene, Reservatrol, Silibilin, Sulforane and the importance of synergy with an eye to the new treatments. The advice is still to use this information to discuss it with the medical team that is following you, where you can also indicate references to supporting scientific works.
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This is an ingredient in the spice of Indian cuisine, turmeric. It has been shown to inhibit the growth of cancer cells of various types in laboratory studies through a number of different mechanisms (272). Like genistein, it inhibits tyrosine kinase signaling and also inhibits angiogenesis. Perhaps most importantly, it inhibits the proteins that prevent damaged cells from undergoing apoptosis, a family of genes known as nuclear factor kappa B. Of all the supplements on this list, it is the most potent anti-cancer agent in studies. laboratory. However, it should also be noted that its bioavailability from oral intake is limited, although presumably the bioavailability is increased when curcumin is combined with piperine (the main ingredient of black pepper). The Life Extension Foundation sells a version of curcumin which, according to them, has far greater bioavailability than anything else on the market. Despite limited bioavailability, there is some evidence of clinical efficacy. In a study of radiotherapy-induced dermatitis for breast cancer, a double-blind, placebo-controlled study compared a placebo with curcumin (2 grams three times / day), both taken during radiation treatment. Significantly fewer dermatitis have occurred in patients taking curcumin.273 Curcumin has also been used in combination with a second supplement, quercetin, (see below) to treat an inherited disease of the colon in which hundreds of adenomas and finally colon cancer (274). Five patients with the disorder received 480 mg of curcumin and 20 mg of quercetin three times a day. The number and size of the polyps were evaluated at the beginning and six months after the start of the supplements. There was a statistically significant decrease in size and number of polyps for all patients.
This is a family of phenolic compounds found in fruit and nuts, including raspberries, blueberries, strawberries, pomegranate juice, and walnuts. In laboratory experiments it has been shown that it potently inhibits the growth of various chemical-induced tumors, with the basis of the effect being an arrest of cell division in phase G, thus inducing programmed cell death known as apoptosis. Although there have been no studies to evaluate its clinical effects on brain cancer, a recent clinical study conducted at UCLA with prostate cancer demonstrates its potential (288). Prostate cancer patients, whose PSA levels were rising after initial treatment with surgery or radiation, drank pomegranate juice (8 ounces / day), which contains high levels of electannins (precursors of ellagic acid) . The dependent variable chosen was the rate of PSA level growth, which typically increases at a constant rate for this category of patients. Pomegranate juice produced an increase in PSA doubling time, from 15 months at baseline to 54 months after consuming the juice. Of the 46 patients in the study, 85% showed a noticeable increase in doubling time and 16% had a decrease in PSA.
Fish oil (source of omega-3 fatty acids)
The main omega-3 fatty acids found in cold water fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have also been shown to have potent cytotoxic effects on cancer cells in various laboratory experiments. . Part of the mechanism of action is similar to that of GLA, as the metabolism of these fatty acids creates high levels of free radicals. Furthermore, a recent laboratory study showed that EPA-treated tumors showed a significant arrest of cell division due to inhibition of cyclins in the G1 phase of cell division, which resulted in an increase in the rate of programmed cell death known as apoptosis (241). A clinical study comparing fish oil supplements with placebo has also been reported, involving patients with several advanced types of cancer (242). Thirty malnourished patients with cachexia were randomly assigned to receive 18g of fish oil per day or a placebo sugar pill. Thirty other subjects, adequately fed, received a similar random assignment. For both groups, fish oil significantly increased survival. For malnourished patients, the median survival times were 110 days for patients receiving placebo and 210 days for patients in the fish oil group. For adequately fed patients, the corresponding numbers were 350 and 500 days. In laboratory studies (243) it has also been shown that fish oil increases the effectiveness of chemotherapy and radiation. A phase II study involving 25 patients with heavily pretreated metastatic breast cancer used 1.8 g / day of DHA, one of the two major fatty acids in fish oil, in combination with standard anthracycline-based chemotherapy (244). Patients had previously failed both chemotherapy and hormone treatments and many had multiple metastases, including many liver metastases. Since it was a phase II study, there was no control group that received chemotherapy alone, but the patients were divided according to their plasma DHA level. The two groups were approximately equal with respect to all major prognostic variables. Median survival for patients with high DHA was 34 months, compared with 18 months for patients with low DHA level. A second clinical study administered 2200 mg of EPA plus 240 mg of DHA to patients with advanced non-small cell lung cancer (245). Patients received only the standard of care of chemotherapy or the same treatment in combination with daily fish oil. The response rate (tumor regressions) was 60% in the group that took fish oil compared to 26% of patients who received standard of care only. One-year survival was 60% in the group that took fish oil compared to 39% in the group that received only chemotherapy. The toxicity of chemotherapy also decreased in the group that used fish oil.
Garlic, like green tea, has been used for its medicinal purposes for hundreds of years. A recent study on cell cultures with glioblastoma cell lines has demonstrated its powerful cytotoxic effects mediated by its ability to induce apoptosis (293). It is also a powerful inhibitor of histone de-acetylase (HDAC).
It is an isoflavone derived from soy products (also found in red clover extract) that has been shown in the laboratory to inhibit the growth of many different types of cancer, including glioma cells. In addition to laboratory evidence, there is substantial epidemiological evidence that a high dietary intake of soy-based products reduces cancer mortality by about 50%. There is also evidence from several clinical trials, mainly for prostate cancer.
Soy extracts containing genistein are available at most health food stores. The concentration of genistein is often not well specified. More importantly, the listed amounts of genistein are so low that they are unlikely to provide clinical benefit. The highest concentration (about 10 times higher than the others I have found) is marketed by the Life Extension Foundation. It may also be possible to buy it wholesale in the form of a product called NovaSoy, manufactured by the Archer-Daniels-Midland Corporation.
Recent experimental studies have examined the mechanisms by which genistein produces its anti-cancer effects (261). The consensus is that this derives from its ability to inhibit the activity of tyrosine kinase. This is a general class of intracellular signals that strongly stimulate cell division. Genistein also appears to produce the inhibition of protein kinase C (discussed previously regarding the mechanisms of tamoxifen). This suggests that a combination of genistein and tamoxifen could be particularly effective. Finally, there is growing evidence that genistein is an angiogenesis inhibitor.
Of particular interest to brain cancer patients is a laboratory study in which glioblastoma cells were treated with a combination of genistein and BCNU (262). The result was a highly synergistic suppression of the growth rate. It has also been shown to increase the effectiveness of other chemotherapy agents (eg, carboplatin, tamoxifen) and other supplements (263).
Green tea has been consumed in both China and Japan for 5,000 years based on its medicinal properties.A recent review summarized its anti-cancer effects in several animal models using both mice and rats (including increased inhibition of cell lines of glioblastoma), both when human tumors have been implanted and when tumors have been induced by various chemical carcinogens (264). In a representative study of chemically induced tumors in mice (265), 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 cancers has been reduced by 30%. The same study identified several mechanisms of action, the most important of which was the inhibition of angiogenesis.
The main active ingredient of green tea is epigallocatechin gallate (EGCG), belonging to a family of molecules known as catechins. Not only has this molecule been shown to be cytotoxic to glioma cells in vitro, but it has also substantially increased the efficacy of both cisplatin and tamoxifen (266).
Of particular interest is a recent in vivo study in which glioblastoma cells were implanted in the brains of mice. Mice were treated with temozolomide alone, EGCG alone, or a combination thereof. EGCG alone did not increase survival time, but its combination with temozolomide significantly increased its effectiveness, compared to that of temozolomide alone (267).
A recent review by the National Institutes of Health’s new division of alternative medicine identified green tea as the most promising of treatments proposed by advocates of alternative medicine. As a result, several clinical studies are underway that study its effectiveness. The only one reported to date has used green tea in the treatment of patients with metastatic androgen-independent prostate cancer (268). The dosage was 6g 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 best with less advanced stages of the disease, and also work better in combination with other therapeutic agents.
A second clinical study used green tea extract at a dose of 2000 mg twice daily with patients diagnosed with chronic lymphocytic leukemia (269). Significant reductions in absolute lymphocyte counts were observed along with substantial reductions in the size of the lymph nodes that reflect the extent of the disease. However, no survival data were reported. Green tea has also been used with patients who have undergone removal of polyps from the colon, or who had previously removed tumors, known high-risk factors for the development of colon cancer (270). Patients received a combination of apigenin (20 mg), a flavonoid most commonly found in celery, and 20 mg of EGCG; the other patients did not receive supplements. Both groups underwent surveillance colonoscopy. In the integrated group (n = -31), only one patient developed an adenoma (7%), while in matched controls (n = 56), 47% of patients had cancer recurrence or adenoma development.
A contraindication for the use of green tea is in combination with Velcade (Bortezomib). Green tea combines with the boron component of the drug, inactivating it (271). However, this interference effect only seems to happen to the Velcade due to its chemical structure.
This is a carotenoid that is found most abundantly in tomatoes but is also found in various other red-colored vegetables (including watermelon). Unlike the better known carotenoid, beta-carotene, it does not transform into vitamin A and therefore has no liver toxicity. In a small clinical trial involving prostate cancer patients about to undergo surgery (281), those who consumed lycopene for several weeks prior to surgery experienced a reduction in both the size and malignancy of their tumors. compared to control patients who did not receive lycopene. In a study of 54 patients with advanced prostate cancer (282), patients were randomized to receive castration or castration plus 2 mg of lycopene per day. Two years after the start of treatment, both groups had reductions in the PSA level of 40% in the group that was castrated only and 78% in the group that also received lycopene. Bone scans also showed greater clinical benefit for the group that received lycopene.
In an experimental study involving both cell cultures and glioma tumors implanted in rats (283) it was found that lycopene (and beta-carotene) substantially inhibited tumor growth in both experimental preparations and indeed had a greater inhibitory effect than that of a set of retinoids commonly used clinically. Of further relevance for gliomas is the fact that one of the mechanisms of action of lycopene is to inhibit the insulin-like growth factor, which as mentioned is involved in the development of resistance to a variety of different treatment agents ( 284). There is also interesting evidence that lycopene synergizes with vitamin D (285).
The only report on the clinical use of lycopene on gliomas comes from a randomized clinical trial conducted in India with 50 patients with high-grade glioma (32 GBM) who received a treatment protocol with radiation and taxol. Patients were randomly divided and a first group received lycopene (8 mg / day) while a second group received a placebo (286). Eighty percent of patients treated with lycopene had complete or partial tumor regressions, while this was true for only 44% of those who received a placebo. Progression-free survival was also higher for those who received lycopene (40.8 weeks versus 26.7 weeks). However, no difference was statistically significant using the a p <.05 probability criterion.
This is a naturally occurring polyphenol that is found most abundantly in grapes and mulberries. Red wine is among the sources. Numerous experimental studies have shown that it inhibits the proliferation of various types of cancer, including glioma, leukemia, prostate, breast and colon. It has also been shown to be synergistic with temozolomide in in vivo rodent studies (291). Among its mechanisms of action are the activation of the P53 gene, the inhibition of protein kinase C and the inhibition of the growth of new blood vessels. In a recent study of its use on implanted gliomas (292), rats received subcutaneous injections or intracerebral injections of tumor cells, which in control animals grew rapidly and became fatal. Administration of a resveratrol dose of 40 mg / kg to the group that received subcutaneous injections of tumor cells resulted in greater growth inhibition with 70% of the rats becoming long-term survivors. A higher dosage (100 mg / kg) was used to inhibit the growth of intracranial tumors but in this case proved only marginally effective. The difference in results in the two cases suggests that resveratrol may be hindered by the blood brain barrier. However, the authors note that it had significant anti-angiogenic effects, which may be independent of the blood-brain barrier. It is not clear whether resveratrol has clinical utility for brain cancer, although various types of anti-angiogenic agents are known to synergize with various types of conventional treatment.
Silibinin (an ingredient in Milk Thistle)
Silymarin is an extract from the milk thistle plant that has been widely used in Europe as an antidote for liver toxicity, due to mushroom poisoning and tylenol overdose. Its active ingredient is a molecule called silibinin. Recently a great deal of laboratory research has shown that it has anti-cancer effects, which have recently been studied (275). Like genistein and quercetin it is a tyrosine kinase inhibitor, but appears to have many other effects, including inhibition of insulin-like growth factor (IGF) which contributes to the development of chemoresistance (276) (see the section on tamoxifen) and inhibition of angiogenesis (277). It also inhibits the inflammatory pathway of 5-lipoxygenase and suppresses the nuclear factor kappa B, which is a primary antagonist of apoptosis (278). It also appears to be able to protect against the toxic effects of chemotherapy (279) and at the same time enhance efficacy (280).
Brassica-based vegetables, which include broccoli, cauliflower, Brussels sprouts, and kale, have long been believed to have anti-cancer properties. A major source of their effects is a substance known as sulforaphane. Recently it was found that 3-4 day old broccoli sprouts contain a concentration of sulforaphane 10-100 times higher than that of adult vegetables. To verify whether oral ingestion of sprouts has anti-cancer effects, dried broccoli sprouts were included in the diet of rats with chemically induced tumors, with the result that a significant regression of tumors was observed (287). Broccoli sprouts are also tasty additions to salads. Other research has shown that sulforaphane is a potent inhibitor of histone desacetylation, which is the target of several new drugs.
The importance of synergy
There is evidence that supplements can be synergistic when used in combination. An experimental demonstration of synergy between glioma cell supplements investigated the combination of resveratrol and sulforaphane (299). Low doses of both in isolation produced moderate cell growth inhibition, but the combination of the same low doses produced greater growth inhibition by a variety of different mechanisms.
The most systematic analysis of the synergistic effect between various supplements targeted two different pancreatic cancer cell lines, known to be highly resistant to treatment. In the first set of experiments, dose-effect functions were independently established for curcumin and soy isoflavones (containing a high level of genistein). As expected, the cancer cells were highly resistant to treatment. Then the combination of agents was tested, using assays that were ineffective in isolation. The combination produced a strong inhibition of cell growth (300). In the second set of experiments the same strategy was used but with four different agents: curcumin, soy isoflavones, resveratrol and EGCG (the active ingredient in green tea). Once again, the combination produced inhibition of cell growth at even lower dosages than those used with the two-way combinations.
Skeptics of dietary supplements / components such as the ones we discussed have argued that laboratory studies providing evidence for their anti-cancer effects have used dosages that can never be achieved in human patients, and therefore supplements are unlikely to be. clinically useful. Without a study of dose-effect relationships in the clinical setting, there is no easy way to evaluate this claim. However, in several cases, researchers have noted that their effects in the laboratory have been obtained with dosages comparable to what is easily achievable with food supplementation, and in several cases there is direct clinical evidence to support them. In any case, for most of the supplements we have discussed there is little or no risk with the only negative aspect of an economic nature. Contrary to the concern expressed by many oncologists, the addition of supplements to standard treatment protocols generally does not interfere with treatment.
Promising new treatments
The above discussion has focused on ways to improve the effectiveness of the Stupp protocol, the standard of treatment for patients with newly diagnosed glioblastoma. While a variety of changes and / or additions to the protocol look promising, none have gained general acceptance. An alternative strategy for newly diagnosed patients is to enroll in clinical trials. While the new treatment agents first studied in clinical trials are unknown quantities, some have preliminary results data that may aid patient decision.Many of the clinical trials also test the new treatment in combination with the standard of care. When I was diagnosed with glioblastoma 20 years ago, few clinical trials looked promising. Now, however, many appear to offer an improvement over the Stupp protocol.
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Fine! I hope you enjoyed reading, I was as faithful as possible. Soon the next chapter!