Natural Compounds and the Future of Cancer Chemotherapy
An evolution in thinking in the field of cancer chemotherapy is bringing conventional medicine and alternative medicine closer together than anyone previously had imagined possible. For fifty years cancer chemotherapy has been dominated by potent drugs that either interrupt the synthesis of DNA or destroy its structure once it has formed. Unfortunately, their toxicity is not limited to cancer cells and normal cells are also harmed. The severe adverse effects induced by these drugs are now well-known. Efforts to develop less toxic drugs that affect only malignant cells have been hampered by our limited understanding of cancer cell biology — cancer treatment has turned out to be more problematic than anyone expected.
Cancer cells are difficult to target exclusively because they are so similar to normal cells. Both proliferate using the same cellular machinery, and destroying that machinery in one destroys it in the other. This is why cancer chemotherapy has failed, in general, to provide high response rates. It rather blindly goes about its business of destroying DNA and the damage it causes to normal cells limits the amount of drug that can be taken. Rapidly dividing cells are particularly affected because their high proliferation rate makes them dependent on frequent DNA synthesis. Thus chemotherapy has been highly successful on fast-growing cancers such as testicular cancer and some forms of leukemia. The majority of adult solid tumors, being relatively slow growing, do not respond nearly so well, however. Rapidly dividing normal cells, including those in the hair follicles, bone marrow, and gastrointestinal lining, are also affected — damage to these account for most of the adverse effects seen.
The excessive adverse effects of chemotherapy have motivated researchers to consider new treatment options. During the last 20 years, efforts to identify the mechanisms that drive cancer cell proliferation have started to uncover the subtleties that make cancer cells unique. This information has led to what can be called a mechanism-based approach to treatment in which each mechanism — each link in the chain of cancer cell proliferation — is a target for therapy.  A whole new generation of mechanism-based drugs is being developed that specifically target cancer cells; such drugs promise to be more effective and have fewer adverse effects than current chemotherapy regimes.
The broadened range of targets within the mechanism-based approach has spurred thousands of laboratories around the world to hope they may discover the magic drug that cures cancer. Such an approach, however, contains a fatal flaw that greatly reduces the likelihood of finding broad cures. Pharmaceutical firms and research institutes are searching for the “silver bullet,” but solutions based on a silver-bullet scheme rarely work as intended in medicine, ecology agriculture, or any other natural science. Even penicillin, the king of silver bullets, is now of diminishing usefulness because of widespread development of bacterial strains resistant to it.  Like microorganisms, cancer cells are quick to develop resistance to monodrug therapies. To find long-lasting solutions to the cancer dilemma, we must shift our thinking to a more organic approach, as, for example, has been done in organic farming where primary emphasis is placed on creating an environment in which insect pests cannot easily survive. This app roach builds the health of the soil and attacks the pest from several different angles, which is, of course, the exact opposite of a silver-bullet approach.
A holistic approach is sure to prevail in the long term. Numerous mechanisms active in a cancer cell allow it to behave the way it does, and just as important, there is intelligence in a cancer cell that enables it to compensate when one of these mechanisms is thwarted. At best, a single drug can target only one or a few mechanisms, and therefore the affected cell retains the ability to adapt. As all researchers and physicians know, cancer cells are excellent adapters. The most effective treatments then are likely to be ones that simultaneously target multiple mechanisms; furthermore, they will redundantly target them. The power of redundancy in population control is a central theme of basic ecology. Mice populations, for example, are far more stable if several natural predators control them. What one predator misses, another picks up.
The Role of Natural Compounds
The mechanism-based approach is perfectly suited to the use of natural compounds. In fact, several natural compounds were used as probes in the initial research that discovered the mechanisms. The term natural compound refers here to a small subset of the hundreds of thousands of compounds that occur in nature (see Table 1). The examples listed all derive from herbs or other natural sources with a history of use as a food or medicine, all are relatively nontoxic, and sound theoretical reasoning exists to support the hypothesis that they may be useful in cancer treatment. These compounds are not only well suited for the mechanism-based approach but also for use in combinations that target multiple mechanisms; each compound tends to affect multiple targets, and combinations redundantly do so. An example of this can be seen in Figure 1.  Here, the five compounds on the left are seen to redundantly affect the seven mechanisms on the right. It is beyond the scope of this article to explain these mechanisms, oth er than to say that PTK, PKC, NF-kB, and [PGE.sub.2] refer to enzymes, proteins, or lipid-soluble compounds that play a role in cell proliferation. The overall effect is clear: natural compounds can be used to provide a multifaceted attack on cancer cells.
This general approach resembles herbal medicine traditions such as those from China and India that have had continuous human application for thousands of years. One might expect that their longevity is due, at least in part, to a certain efficacy. There is little scientific reason to believe, however, that simply brewing a tea from a mixture of herbs will provide an effective cancer treatment. Cancer is a difficult disease, and for natural compounds to be effective, they will need to be used as part of a well-honed strategy. For example, pharmacokinetic analysis for many of these compounds reveals that relatively high doses will be required.  High doses and the need for precise dosing necessitate that semipurifled and standardized extracts of these compounds be employed.
Used in strategic combinations, there is good scientific reason to believe that natural compounds could inhibit cancer. Hundreds of animal studies and dozens of human studies point to their potential.  Importantly, synergism has been demonstrated when combinations of compounds are used, and synergistic interactions are key to their effective application.  The use of large combinations is, of course, the antithesis of the silver-bullet approach. Drug developers looking for such will quickly pass by these natural compounds; they will also be disregarded because few are patentable, a requirement due to economic constraints. Drug developers invest millions of dollars in studies to bring a drug to market, and they recoup this investment through licensing, which requires a patent. Since patents are given only for new and unique molecules, and since natural compounds are far from new, patents are difficult to obtain. Use patents (patents on a particular application of a compound) are easier to get, but these a re not as valuable as patents on the structure itself. There are several reasons then that natural compounds are not thoroughly evaluated for their anticancer potential.
To overcome these obstacles will require a concerted effort by the public and by interested members of the scientific community. Fortunately, this effort is well under way. Interest in the chemistry and pharmacology of natural products is higher than it has been in decades, and new studies are published daily that fill gaps in our current understanding. Public interest is also growing rapidly. A recent survey estimated that more than 60% of cancer patients use vitamins or herbs at some point in their therapy.  As additional studies are published and the body of evidence grows, interest in natural anticancer compounds can be expected to grow. What remains to be seen is whether the silver-bullet approach will prevail. If it does, we risk overlooking the great value that natural compounds offer to medicine. It is time to open our minds wider and to question our approaches more deeply than we have ever done. In so doing, we revitalize the possibility of merging the wisdom of the past with the achievements of t he present.
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(3.) Boik J, Natural Compounds in Cancer Therapy. Oregon Medical Press, Princeton, MN, 2001, p. 158.
(4.) Boik J, Natural Compounds in Cancer Therapy. Oregon Medical Press, Princeton, MN, 2001, pp. 445-84.
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Example Natural Compounds of Interest
Compound Brief Description
Apigenin Flavonoid found in many plants,
Arctigenin Active compound in burdock seeds
Astragalus membranaceus Herb used as an immunostimulant in
Chinese herbal medicine.
Boswellic acid An active compound in frankincense
(Boswellia carteri or B. serrata).
Caffeic acid phenethyl ester (CAPE) An active compound in bee propolis.
Curcumin An active compound in the spice
tumeric (Curcuma longa).
Eleutherococcus senticosus Herb with immunostimulant
properties; also known as Siberian
ginseng and Acanthopanax senticous.
Emodin An active compound in the herb
Polygonum cuspidatum and in other
EPA and DHA (eicosapentaenoic and Omega-3 fatty acids that are found
docosahexaenoic acids) together in fish oil. Of the two,
EPA is of primary interest in
Ganoderma lucidum Mushroom used in Chinese herbal
medicine that has immunostimulating
Genistein and daidzein Isoflavonoids found in legumes such
Ginseng (Panax ginseng) Herb with immunostimulant
Luteolin Flavonoid found in many plants,
including chamomile and rosemary.
Melatonin Hormone used clinically to induce
Monoterpenes Fragrant essential oils;
Monoterpenes include limonene,
perillyl alcohol, and geraniol.
Parthenolide An active compound in the herb
feverfew (Tanacetum parthenium).
PSP and PSK Mushroom extracts (obtained from
Coriolus versicolor) that have
Quercetin Flavonoid found in many plants.
Resveratrol A compound found in wine and grapes
in the herb Polygonum cuspidatum,
and in other herbs.
Selenium Trace element that plays a role in
the body’s antioxidate system.
Shiitake (Lentinus edodes) Mushroom that has immunostimulant
Vitamin A Vitamin important in vision, cell
proliferation, and immune function.
Vitamin D3 Vitamin important in calcium uptake
that has antitumor propperties.
COPYRIGHT 2001 The Townsend Letter Group
COPYRIGHT 2008 Gale, Cengage Learning