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Complex, multiple drug “cocktails” are standard in oncology, because researchers and clinicians have realized that cancers operate through multiple biochemical and physiological mechanisms. In a way, these multi-drug combos could be seen as a high-tech attempt to replicate the complexity of medicinal plants.
Serious study of antineoplastic medicinal plant extracts is still in its infancy, but a growing body of research already shows that herbs have multiple effects all of which can potentially be leveraged to prevent or treat some forms of cancer.
The Center for Holistic Urology at Columbia University is at the forefront of this work. Led by Aaron E. Katz, MD, researchers there have been studying a number of standardized plant medicines for prostate cancer, the second leading cause of cancer-related deaths among American men. The two stars of the recent Columbia studies are Prostabel and Zyflamend.
COX and Cancer
Zyflamend is a standardized combination of 10 supercritical CO2 whole-plant extracts originally marketed as a natural alternative to Vioxx and other non-steroidal anti-inflammatory drugs. The formula includes turmeric, ginger, rosemary, holy basil (tulsi), oregano, skullcap, and other herbs all of which have inhibitory effects on cyclooxygenase (COX) 1 and 2 enzymes.
Dr. Katz and his team originally became interested in Zyflamend several years ago, because certain forms of cancer, including some prostate cancers, are associated with high COX-2 levels. This enzyme, which mediates the conversion of arachidonic acid into inflammatory prostaglandins, also affects genes that regulate cellular growth, proliferation, differentiation and angiogenesis.
Several COX-2 inhibiting pharmaceuticals have been shown to inhibit growth of prostate cancer in vitro, and on a population level, people who regularly take COX-2 inhibitors have lower incidence of certain cancers. The Columbia team reasoned that a botanical COX inhibitor might provide similar anticancer effects without the side effects associated with NSAIDS.
Dr. Katz’ team showed Zyflamend has independent but non-selective COX-1 and COX-2 inhibitory effects, and that it can inhibit growth of prostate cancer cell lines by as much as 80%. The plant combination inhibits angiogenesis and promotes apoptosis. Pre-clinical work was sufficiently compelling to prompt a clinical trial of Zyflamend to prevent progression of prostate intraepithelial neoplasia (PIN) to frank prostate cancer. If untreated, PIN has progression rate of 40%–60% per year. The trial is underway, and Dr. Katz said early results are encouraging.
Zyflamend: COX-Independent Apoptosis
The newest piece of the Zyflamend picture is the discovery that it induces apoptosis in prostate cancer cells independent of its COX effects. Debra Bemis, PhD, a member of the Columbia team studied LNCaP cell lines (a common human prostate cancer line), and found that while the herbal combination reduced COX-1 and COX-2 expression, it also increased cell cycle inhibitory protein p21 (an inducer of apoptosis). Poly ADP-ribose polymerase (PARP) fragments were also present in Zyflamend treated cells, as was Caspase-3, both of which are consistent with apoptosis.
The apoptotic changes were clearly independent of COX activity; Dr. Bemis added prostaglandin E2, the primary inflammatory signal produced by COX-2 pathways, and even at high concentrations, it did not reverse apoptosis (Bemis DL, et al. Nutrition and Cancer. 2005; 52(2): 202–212). Zyflamend also reduced androgen receptor levels by 40%. This is important given that prostate cancer growth is driven by androgen action. She presented the findings at the recent Scripps Clinic Natural Supplements conference.
Though she is studying prostate cancer at the molecular level, Dr. Bemis also keeps an eye on the big picture. “One of the more interesting aspects of prostate cancer is the fact that latent prostate cancer occurs at equal rates in both Asian and American men, whereas incidence of clinically significant prostate cancer is much greater in the US than in Asia. There are reasons to believe this is related to the dietary intake of the different populations.”
She pointed out that typical Asian diets contain far greater amounts of ginger, turmeric, green tea, soy and other plant foods with anti-cancer effects, but much lower intake of animal fats, trans fats and other pro-inflammatory foods. A product like Zyflamend, though not a substitute for a healthier diet, brings the anti-inflammatory and anti-cancer benefits of many key components of an Asian diet together in an easy-to-use form.
Prostabel: Repairing Destabilized DNA
More recently, the Columbia team began looking at Prostabel, a standardized combination of compounds from Rauwolfia and Pau Pereira, a tree from the Amazon rain forest. The Katz group has shown that Prostabel can markedly reduce prostate cancer growth in vitro and in animal models, but it appears to do so by very different mechanisms from Zyflamend.
Prostabel was initially formulated by the late Dr. Mirko Beljanski, a visionary cell biologist who studied cell regulation and replication at the Institut Pasteur in Paris from the 1940s through the late 70s. Dr. Beljanski’s primary discovery, one that put him at odds with mainstream genetics, is that DNA in cancer cells shows 3-dimensional structural differences from DNA in normal cells. In cancer cells, it has many more broken hydrogen bonds between the helical strands, creating permanently open loops that permit uncontrolled replication. The separation between the strands can be induced by carcinogenic substances.
While the vast majority of geneticists and cancer biologists focused on mutations, that is, changes in the actual nucleotide coding sequences, Dr. Beljanski stressed the importance of structural changes, insisting that loose DNA loops could lead to neoplasia even in the absence of cancer-causing mutations.
“In a sense, Beljanski went down the other fork in the (genetic) road, looking at things that cause cancer without causing mutations. He was looking outside the mutagenic theory,” explained John Hall, PhD, a cell biologist formerly at Rockefeller University, who is now Director of Research at Natural Source, the company founded by Dr. Beljanski’s family to carry on his work and bring the botanical medicines he discovered to market.
Before he died in 1998, Dr. Beljanski screened hundreds of plants looking for compounds that could inhibit or repair the DNA strand separation induced by carcinogens. “While he was at Pasteur, someone came to him wanting to know if Rauwolfia (the African plant source of reserpine), was carcinogenic,” Dr. Hall told Holistic Primary Care. “He actually found something in this plant that acted like an anti-carcinogen.”
That substance turned out to be an alkaloid called alstonine. He later found a similar compound called flavopereirine, in the bark of the Pau Pereira (Platycyamus regnelii) tree, used as medicine by indigenous Amazon peoples. Both compounds have bipolar charges, which is key for targeting cancer cells.
“We’ve got assays showing how these compounds bind to DNA. We know they concentrate in cancer cells, but not in normal cells. Cancer cells have very different charge distributions,” said Dr. Hall. “Compounds from Rauwolfia were considered as dyes to mark tumors, so this is not such a radical idea.”
He has been working with Dr. Bemis and the Columbia team to design studies to validate Dr. Beljanski’s original findings. They have already shown that Prostabel kills prostate cancer cells in vitro, and can reduce tumor volume in human prostate cancer xenografts in nude mice. A clinical trial of Prostabel to prevent prostate cancer in men with elevated PSAs is in the works.
“We don’t yet have nearly enough clinical data on this product,” acknowledged Dr. Hall. “We do have considerable anecdotal data from men in prostate cancer support groups, and we’ve tracked PSA changes over time. Most of this comes from France, where the Beljanski formulas have been available for years. The most famous user was former French President François Mitterrand, who had advanced, metastatic prostate cancer. “One of his doctors decided to try the Beljanski formula in conjunction with conventional drugs. It prolonged his life for two years, and allowed him to complete his term,” said Dr. Hall.
Though Natural Source sees potential for Prostabel as a preventive therapy, the anecdotal data collected so far suggest it’s best current indication is as an adjunct to standard chemo and radiation therapy. This is in accord with Dr. Beljanski’s original vision.
“Beljanski was not a nut. He didn’t promote these plant medicines as a panacea, and he was not unrealistic in his expectations. He was looking for synergies with conventional chemotherapy. But he was very far-sighted. He knew, far back, that cancer was a complex disease, and treatment would require a cocktail approach.”
Prostabel and several others of Dr. Beljanski’s formulas are available from Natural Source (www.natural-source.com, Tel. 212-813-2047). Zyflamend is available from NewMark (www.new-mark.com, Tel. 866-963-9675).
