WESTERN COUNTRIES LEAD THE WORLD IN METASTATIC PROSTATE CANCERS

Although the occurrence rate of localized, latent form of prostate cancer is consistent throughout the world, the occurrence of metastatic prostate cancer is much greater in western countries compared to eastern countries. This striking disparity suggests the involvement of environmental factors in the development of metastatic prostate cancer, and has prompted the initiation of several epidemiological studies. Data collected from these studies, as well as many in vivo and in vitro laboratory experiments, suggest a link between high fat diets and risk of metastatic prostate cancer. Both arachidonic acid and its precursor, linoleic acid, are present in significant quantities in animal fats and a variety of vegetable oils. Physiologically, these fatty acids are integral components of cellular membranes and also function as substrates for the production of an important group of potent, signaling lipids, termed eicosanoids. Eicosanoids are known to be involved in the initiation of the inflammatory response, fever production, regulation of blood pressure, blood clotting, control of reproductive processes and tissue growth, and regulation of the sleep/wake cycle. Additionally, these powerful mediators and the enzymes that produce them, cycloxygenases (COX) and lipoxygenases (LO), have recently been implicated in tumor development, progression, and metastasis.

COX-2 IMPLICATED IN MANY DISEASE STATES INCLUDING CANCER

The two main isoforms of cycloxygenase are COX-1 and COX-2, and these enzymes are responsible for the production of the group of eicosanoids, prostaglandins. The COX-1 isoform has many important 'housekeeping' functions in the cell, and is therefore constitutively produced throughout the body. COX-2, however, is usually absent until induced by pro-inflammatory stimuli. It is therefore not surprising that COX-2 is implicated in the progression of many disease states, including cancer. COX-2 has been found to be present in elevated levels in a variety of cancers thus far, including lung, colon, pancreatic, and head and neck, and prostate cancer. In regards to prostate cancer, numerous studies have demonstrated elevated levels of COX-2 in tumor samples. COX-1 expression has also been observed to be elevated in tumor samples, however at this point, the data is not as extensive as that available for COX-2. Interestingly, benign tissue obtained from the same prostate cancer patients was found to have significantly lower levels of COX-2, demonstrating an increased level of enzyme expression with disease progression. Other studies have suggested that COX-2 activity and resultant prostaglandin production is involved in tumor-induced angiogenesis, or new growth of blood vessels to supply the tumor. Additionally, some COX-2 inhibitors have been observed to re-initiate a cell death program ultimately leading to cell suicide. Data such as these have lead many researchers to consider these enzymes as useful targets for novel chemotherapeutic development.

Preliminary data from these early studies suggests that Zyflamend is inhibiting cell growth in the prostate cancer cell line and potentially initiating apoptosis. The centuries old natural remedy of using white willow bark (Salix alba) to provide some pain relief led to the discovery of aspirin, and eventually, to the elucidation of its mechanism of action as a COX inhibitor. Based on this lead and other traditional Eastern medicinal practices, many researchers have looked to a variety of natural plant extracts and natural products for the discovery of both non-specific COX and specific COX-2 inhibitory activities. Some herbal extracts and natural products that have peaked interest amongst researchers include curcumin (turmeric), ginger, holy basil, resveratrol (high abundance in grape skins), thundergod vine, and berberine (from barberry and Chinese goldthread). One company in particular, New Chapter Inc. (Brattleboro, VT), has prepared a promising mixture comprised of ten different herbal extracts of which most are potential COX-2 inhibitors. This dietary supplement, Zyflamend, is also unique in that it is prepared via supercritical CO2 extraction. Unlike traditional solvent based extraction methods, supercritical CO2 extraction allows the natural products in the herbs to be obtained without leaving chemical residues behind in the preparation. In the laboratory, we have recently begun to evaluate this preparation for COX-2 inhibition in a prostate cancer cell line. Additional end points that we are investigating include the potential of Zyflamend to induce apoptosis (a programmed cell death pathway that cancer cells have learned to override) and inhibit cell growth. Preliminary data from these early studies suggests that Zyflamend is inhibiting cell growth in the prostate cancer cell line and potentially initiating apoptosis. We look forward to continuing these studies and reporting back on the COX-2 inhibitory activity of Zyflamend and other natural extracts. We also plan to further analyze Zyflamend for 5-LO inhibitory activity and will discuss more on these studies and their relevance to prostate health in future issues.