The Role of Natural Products in the Treatment of Cancer

Cancer medicine utilizes small molecules as therapeutics. Many compounds in use today are derivatives of plant alkaloids. Among the most widely used drugs derived from plant alkaloids are the taxanes, vinca alkaloids and topoisomerase inhibitors. Antibiotic anti-tumor agents including anthracyclines, Bleomycin and Mytomycin-C have been isolated from streptomyces bacterial cultures. Several antimetabolites also have their origins in natural products.

It is evident that nature is an excellent source of effective treatments. Unfortunately, there has been hesitancy on the part of the conventional oncology community to incorporate other natural products into therapeutics. Nonetheless, a wide variety of plant extracts have significant anti-tumor activity. Among the compounds under investigation are the cyclic triterpenes, mono- and di-terpenes, as well as stilbenes and derivatives of scutellaria and glyzrrha. In addition to cytotoxic activity, many plants are effective in chemoprevention. Extracts of grape (resveratrol), chocolate, green tea (catechins), as well as colored fruits (anthocyanins) and berries (ellagic acid) can elicit protective responses, some mediated by the KEAP-1, NRF-2 pathway. Click here to read a previous article that discusses the medicinal qualities of garlic, wine and chocolate.

The arbitrary distinction between commercial therapeutics and nutritional substances has created an unnecessary barrier between conventional therapists and those who practice complimentary care. A growing cadre of physicians is developing expertise in natural product therapeutics in parallel to their traditional training. Chinese herbal and Indian ayurvedic medicine instruct physicians in the appropriate use of natural therapies. An explosion of interest in resveratrides, curcuminoids and terpenes are fueling a rebirth of interest in these naturopathic approaches.

As an editor of the Journal of Medicinal Food, I have contributed to the literature on the medicinal value of foodstuffs and natural products. Original articles on the benefits of garlic have been followed by the study of the monoterpene limonene and contributions on Chinese herbal medicines, chocolate extracts and grape seed extracts. Our laboratory has been engaged in the formal analysis of many natural products and we have reported exciting results with several classes of compounds. In one instance, an Australian extract was administered successfully in the treatment of advanced renal cancer under FDA IND. We are convinced that an exciting opportunity for cancer treatment exists in the formal study and rigorous evaluation of these biologically active molecules and combinations.

Horizontal and Vertical Signal Pathway Inhibition

The importance of signal pathway inhibition in human tumor primary culture microspheroids.

Signal transduction pathways are important targets in cancer therapy. Small molecule inhibitors for the tyrosine kinase and serine threonine kinase pathways are already available for clinical therapy. Additionally, compounds targeting the PI3K, AKT and MEK pathways will be available in the coming years. To explore the interaction of these parallel survival pathways, we compared activity and combined these inhibitors in human tissues — the results were instructive.

Our findings include favorable interactions between EGFr tyrosine kinase inhibitors and compounds that block the PI3K pathways. The most active combinations were those that inhibited the cross-talk between pathways (horizontal inhibition) over drug combinations that targeted the same pathway at different downstream points (vertical inhibition). Similar observations have been made combining PI3k inhibitors and MEK inhibitors. One such report in PNAS (May 10, 2010) closely paralleled the work conducted in our laboratory, Rational Therapeutics, that we reported at the AACR.

Noteworthy, a series of studies utilizing these combinations, indicate that certain tumors respond to their drug exposure by undergoing autophagic death, not necrotic or apoptotic. This distinction is possible, as the Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) platform has the capacity to measure all forms of cell death – apoptotic and non-apoptotic.

We continue these studies in numerous solid tumors to explore those diseases that will be the best candidates for these types of combination therapies. Please leave a comment below if you would like more information on these studies.

Is Metastatic Colon Cancer Curable?

Following the introduction of 5FU in 1958, response rates for metastatic colon cancer remained in the range of 12-14 percent. After several decades, the addition of Leucovorin to 5FU improved these response rates to 20 percent. Optimal infusion schedules further enhanced responses providing objective benefits in 20-30 percent of patients. Subsequent to the introduction of Irinotecan and later Oxaliplatin, colon cancer response rates are now observed in 40-50 percent of patients — even higher in some series.

This has spawned a new interest in post-chemotherapy surgical cytoreduction. Under these circumstances, patients who present with Stage 4 disease (most often metastatic to liver) undergo aggressive combination therapy — usually Folfox-based. Those achieving substantial response (complete or partial) are then considered for partial hepatectomy to reduce residual tumor burden. In a series of trials conducted by large institutions like MD Anderson, a subset of patients is now achieving durable complete remissions using this multi-modality approach.

One example of this approach represents a novel opportunity to explore the biology of this disease.

Case Report
A 44-year-old previously healthy male presents with T3, N2, M1 colon cancer with multiple positive lymph nodes and a liver metastases. Despite the primacy of Folfox-based therapies in this setting, functional profiling of his tumor revealed superior activity for the dual modulation of Irinotecan activity with Erbitux and Avastin After several cycles of therapy, all disease had disappeared with the exception of a small residual focus in the liver.

The patient underwent a partial hepatectomy and tissue removed at the time of surgery was re-examined in the laboratory. The Ex-Vivo Analysis of Programmed Cell Death (EVA-PCD®) functional profile results had completely changed, now favoring Folfox over Irinotecan-based therapy. Following surgical recovery, the patient was provided post-operative adjuvant Folfox.

Today, more than two years since diagnosis, all biochemical and radiographic restaging reveals no evidence of disease. While the patient will require continued surveillance, he represents a genuine advance in the management of this disease and may escape recurrence. This allows him to continue a normal life, despite a diagnosis that a decade earlier would have been considered a death sentence. Cases like this will ultimately enable us to answer the question: Is metastatic colon cancer curable?

Garlic, Wine and Chocolate – The Effects of Nutrition on Cancer

One of my most popular lectures is titled: Garlic, Wine and Chocolate. Not surprisingly, almost everyone likes to have a medical reason to eat fine food, drink fine wine and eat dessert. As an editor of the Journal of Medicinal Food, our mission is to examine the scientific basis of foods as medicinal substances.

In our inaugural issue in 1998, I authored the lead article on garlic as a medicinal. Garlic contains more than a dozen active chemical substances, many of which have been shown to have antiviral, antibacterial, blood pressure and cholesterol lowering, as well as anti-cancer benefits. We have also published definitive studies on wine and grape extracts, with a focus on resveratrol, proanthocyanins and other polyphenols; as well as an entire issue on chocolate (the extract of cacao), which examined the potent antioxidants and immune modulatory compounds found therein.

With this background, lectures on these topics have been a natural direction for our public education series through our affiliated hospitals and educational institutions. For readers in the Southern California area, you are invited to attend lectures of this type open to the public. Please leave a comment if you are interested in more information or copies of the above-mentioned articles.