July 8, 2011

Researcher looks to vegetable and spice derivatives to combat cancer

Mom really was on to something when she admonished us to eat our vegetables because they were good for us.

While millions of mothers have cajoled their children to dig into the veggies on the basis of good nutrition, a Wayne State University School of Medicine researcher is taking that advice more than a few steps further by developing compounds from them to make the fight against cancer more efficacious.

Fazlul Sarkar, Ph.D., professor of Pathology and Oncology, for the School of Medicine and the Karmanos Cancer Institute, studies natural agents found in a variety of vegetables and a spice that can decrease tumor growth and greatly enhance the effectiveness of chemotherapy or radiation therapy treatments. Dr. Sarkar's research stemmed from many years of research on the development of active agents against cancer discovered from the bounties of nature. However, what nature can offer in terms of novel chemotherapeutic agents has not been fully exploited.

The National Cancer Institute, National Institutes of Health - Natural Products Repository houses some 170,000 extracts from samples of more than 70,000 plant and 10,000 marine organisms collected from more than 25 countries, as well as more than 30,000 extracts of diverse bacteria and fungi. This repository is considered to be the source of novel compounds to add to the 500,000 compounds envisaged for the NIH Roadmap Molecular Library.

After more than 40 years of screening these extracts, a critical arsenal of cancer drugs has been developed. That arsenal was led by the flagship drug Taxol, which has been approved by the Federal Drug Administration for the treatment of several human malignancies. Many other drugs originally discovered from nature have also been approved by the FDA, including camptothecin and its analogs (topotecan and irinotecan), vinblastine and vincristine, and microbial-derived anthracyclines such as doxorubicin and the bleomycins. Several other promising compounds are in testing in clinical trials against cancer and other deadly diseases such as AIDS. Interestingly, it has been estimated that more than 60 percent of approved anti-cancer drugs are derived in one way or another from natural sources, and thus far, natural products chemistry has proved superior to that of combinatorial chemistry, Dr. Sarkar said.

The large proportion of natural products in drug discovery has stemmed from the diverse structures and the intricate carbon skeletons of natural products, especially flavonoids, coumarins and indoles, and increasing evidence suggests that natural compounds are superior for further drug development. Agents derived from natural sources could be very useful for the treatment of human malignancies either alone or such agents could be useful as an adjunct to conventional therapeutics, both chemotherapy and radiation therapy. Keeping abreast of emerging and rapid advances in the synthesis, characterization and testing of many such agents that are coming through the drug pipeline through exploitation of natural sources became important for Dr. Sarkar's focused research on specific and novel classes of compounds derived from both natural resources as well as from the tables of synthetic medicinal chemists, which could become newer arsenals for fighting the battle against human malignancies.

The compounds so far examined by Dr. Sarkar -- found in soy, leafy vegetables, cruciferous vegetables like broccoli and Brussels sprouts, hot peppers and curcumin, an ingredient in the spice turmeric -- work by making cancerous tumors more sensitive to the attacks of chemotherapy and radiotherapy and in most cases cause cancer cell death while protecting normal cells.

Dr. Sarkar, whose research is currently funded by five NIH-RO1 grants, has demonstrated that combining genistein (isoflavones), a component of soy, with the chemotherapy drug oxaliplatin causes pancreatic cancer cells to react more sensitively to chemotherapy. The finding is exciting because pancreatic cancer, a malignant tumor within the pancreatic gland, is often considered the most deadly form of cancer. Depending on the extent of the tumor at the time of diagnosis, the prognosis is generally regarded as poor. Few victims are still alive five years after diagnosis, and complete remission remains extremely rare.

According to the NCI, 43,140 Americans were diagnosed with pancreatic cancer, and 36,800 died from the disease in 2010. Pancreatic cancer remains the fourth leading cause of cancer deaths in men and the third leading cause of cancer deaths in women in the United States. Only 15 percent of pancreatic tumors are surgically removable. About 15 percent to 20 percent of patients who undergo surgery survive five years after the treatment. The average survival of patients with a more advanced stage of the disease is only six months.

The rates of incidence and mortality related to pancreatic cancer have remained relatively constant over the last 30 years. The NCI says that one in every 71 Americans born today will be diagnosed with cancer of the pancreas. Only about 4 percent of those diagnosed survive. Chemotherapy remains a standard of treatment despite the dire outcomes.

Dr. Sarkar's research with genistein (isoflavones), however, shows promise in making chemotherapy more effective in combating the tumors, and not just in pancreatic cancer -- breast, prostate and other types of cancer cells have also demonstrated sensitivity to the compound.

The soy derivative, he explained, works by limiting the cancer cell's ability to mutate in an attempt to battle chemotherapy drugs. In effect, it weakens the cancer cell's defensive mechanisms. In an animal model, pre-treating pancreatic cancer cells with genistein and then with oxaliplatin increased cancer cell death and reduced the spread of the cancer into lymph nodes.

Dr. Sarkar does not claim these naturally occurring compounds and their synthetic variations have the ability to cure cancers. Instead, they appear to have an adjuvant characteristic that assists chemotherapy treatments by inhibiting a cancer cell's ability to mutate to fight treatment. Similar observations on isoflavones have also been made with radiotherapy in prostate and renal cancer models.

"Think of it in terms of a flood," he said. "The chemotherapy is the water and it seeks to flood the cancer cells. The cells, in reaction, throw up sandbags (mutate) to block the flow, and they are very good at setting up those sandbags. Water, however, will continue to seek openings in the sandbag wall, and if these compounds can knock down enough sandbags, then the chemotherapy chemicals can become more effective."

He has tested soy isoflavones in sensitizing prostate cancer cells to radiation therapy. The isoflavones works by inhibiting cell survival pathways activated in response to the attack by radiation. Simultaneously, the isoflavones from soy showed antioxidant and anti-inflammatory characteristics, which can help prevent or diminish the adverse side effects of radiation therapy on normal cells.

In a clinical study, 42 patients with localized prostate cancer were selected to randomly receive 200 milligrams of soy isoflavones or a placebo daily for six months starting on their first day of radiation therapy. At each point during the study, the men who received the isoflavones reported decreased urinary, bowel and incontinence side effects, and better erectile function, than their counterparts who received the placebo.

"I really think that we are only scratching the surface as to the potential compounds in plants that can assist us in winning the battle against cancers," said Dr. Sarkar, who has been engaged in this field of research for more than 20 years.

His research using compounds derived from green leafy vegetables called Indole-3-Carbinol (I3C), which is readily converted to its self-dimerized compound, 3.3'-diindolylmethane (DIM) in the stomach, showed dramatic effects in preclinical studies. Since then, Dr. Sarkar, in collaboration with BioResponce LLC and Elisabeth Heath, M.D., associate professor of Oncology for the Wayne State University School of Medicine and director of Prostate Cancer Research at the Barbara Ann Karmanos Cancer Institute, has developed an improved formulation of DIM, which he has tested in a Phase I clinical trial in prostate cancer patients. Based on non-toxic dose calculation, he also has initiated a Phase II clinical trial at Karmanos Cancer Institute in collaboration with the Urology Department at Henry Ford Health System in patients diagnosed with prostate cancer. The preliminary results are "very encouraging," Dr. Sarkar said.

He and his research colleagues have also tested extracts from a number of peppers and found that capsaicin too induced significant growth arrest and cell death in human breast and leukemia cancer cell lines, with no significant effect on normal cells. Capsaicin, the active component of peppers such as jalapenos and habaneros, is found mainly in the white pith that surrounds the internal seeds of such peppers. The compound can irritate and burn the skin, mucous membranes and eyes - hence its use in pepper sprays used by police departments. The rate of cancer cell inhibition and death, Dr. Sarkar found, correlated with the capsaicin content, based on the Scoville scale - a measurement of the hotness of peppers. The hotter the pepper from which the capsaicin is extracted, the more potent in knocking down the defensive mechanisms of the cancer cells. The results, he said, warrant additional research into the potential use of pepper extracts as anti-cancer agents.

Another compound showing promise in the fight against cancer can commonly be found in Indian cuisine. Curcumin, the major active ingredient in the spice turmeric, Dr. Sarkar has found, arrests the growth of cancer cells and promotes cancer cell death. However, the compound in its natural state is rapidly processed by the body, so its ability to remain and engage in the fight is relatively weak.

To overcome that weakness, Dr. Sarkar's lab synthesized a novel curcumin analogue called CDF, which remains in the body longer, is absorbed more readily into the blood stream, and demonstrates a greater efficacy in diminishing the defensive mechanisms of cancer cells and causing cancer cell death when used in conjunction with chemotherapy treatments. He is now working to have CDF further synthesized into a drug to be taken in conjunction with chemotherapy for pancreatic, prostate and colon cancer. His research on CDF has been published in many high-impact journals, and he secured a five-year NIH-R01 grant which began July 1.

Dr. Sarkar, in collaboration with Adhip Majumdar, Ph.D., professor of Internal Medicine at the School of Medicine and the Karmanos Cancer Institute, and senior research career scientist at the Veterans Administration Medical Center, recently published in the journal Translational Oncology and Pharmaceutical Research findings that show the use of curcumin or CDF, either alone or in combination with standard chemotherapy in chemotherapy-resistant colon cancer cells, resulted in the killing of cancer cells that have a cancer stem-like cell quality. The findings are similar to those he published using pancreatic cancer cells. The colon cancer cells resist conventional chemotherapy and have the ability to renew themselves. They also provide a path for malignant cells to propagate and spread. Knocking out the stem-like cancer cells with a curcumin analogue, however, requires developing a compound that remains in the blood stream longer. He said that while curcumin has good absorption rates in the gastrointestinal system, it has very low absorption rates in the blood stream, with levels peaking and then disappearing within 30 minutes to an hour. His newly developed CDF compound raises hope in the fight against human malignancies.

While the produce aisle appears to hold plenty of promise for combating cancer -- Dr. Sarkar said he and his wife have added to their own diet some of the vegetables that are the originators of the compounds he studies -- he cautioned that fighting cancer isn't as simple as ingesting massive amounts of soy, spinach and tumeric.

"You'd have a very difficult time eating as much curcumin in your diet as the amounts we synthesize for the compounds we are testing to facilitate the development of natural agents or their synthetic derivative as newer drugs that could be used alone as chemotherapy or could be an adjunct to other conventional therapeutics," he said.

But adding more vegetables to your diet can't hurt and definitely has its benefits. Just ask Mom - and Dr. Sarkar.