Dietary Indole Analogs for Breast Cancer Prevention

Institution: SRI International
Investigator(s): Ling Jong, Ph.D. -
Award Cycle: 1998 (Cycle IV) Grant #: 4KB-0040 Award: $435,595
Award Type: New Investigator Awards
Research Priorities
Etiology and Prevention>Prevention and Risk Reduction: ending the danger of breast cancer

Initial Award Abstract (1998)
Prevention is the best way of dealing with any disease, and this is particularly true of cancer, with all of its complexities and its often devastating course. Numerous studies suggest an effective role for fruits and vegetables in the prevention of human cancer, especially breast cancer. Such preventive effects are very likely to come from tumor inhibitors that occur naturally in food and plants. Dietary natural products are presumably safe, and thus are very attractive as the lead compounds for developing novel cancer preventive agents.

Indole-3-carbinol (I3C), a dietary component found in cruciferous vegetables such as cabbage, broccoli, and Brussels sprouts, has a striking ability to prevent breast cancer in various laboratory models, and it is currently undergoing Phase I clinical trials for breast cancer prevention in humans. However, I3C itself is far from an ideal breast cancer preventive agent. One serious drawback is that the compound itself is not active against cancer but must be acted on by gastric acid in the stomach to produce the active forms, and it is not known which of its many digestion products is the most important for cancer prevention. Furthermore, the cancer preventive effect may vary considerably between individuals, and at different times in the same individual, because variation in gastric contents could substantially affect the formation of the active forms. Clearly, there is room for improvement.

This research project aims to develop a safe, effective reliable breast cancer preventive agent based on I3C and four of its known active forms. We have found some important structural similarities in the four active forms by using computer modeling and analysis, and we plan to use one active form as the framework and modify it with carefully designed changes. Our goal is an I3C derivative that can be taken orally, retains the ability to inhibit activities associated with cancer onset, and has improved stability, increased clinical effectiveness, consistent results, and minimal toxicity and side effects. This novel breast cancer prevention candidate will be unique because it is a derivative of a dietary natural product whose history of consumption by humans for centuries indicates it is likely to be safe for long-term use.

Our multidisciplinary approach combines lead-based compound design, medicinal chemistry, computer modeling, cell culture biological screening, and tumor biology. The systematic development of compounds is coupled with basic research into mechanisms of action and feedback of the findings to guide design and discovery of improved compounds. Achievement of our goals could have a significant impact on reducing the human and economic costs of breast cancer in California.

Final Report (2001)
The continuing rise in the incidence of breast cancer supports the need for placing a high priority on research aimed at its primary prevention, particularly among women who are at high risk for developing this disease. Chemoprevention, the use of pharmacologic agents for long term administration to inhibit the development of cancer, has become an increasingly important priority for the California BCRP. The objective of this grant was to develop a new class of safer cancer preventives.

We aimed to develop a novel cancer preventive drug by improving upon a dietary component called indole 3 carbinol (I3C), which has known anticancer activity but I insufficient potency. We have been very successful in developing indole analogs with more potency against various human breast cancer cell lines. In animal models, these indole drug candidates have demonstrated potent antitumor activity and acceptable oral bioavailability, the most desired property for cancer preventive agents. Such a diet derived drug should have an excellent likelihood of being safe for long term use.

In Years 1 and 2, we designed and synthesized a variety of indole analogs and used molecular modeling to identify several important parameters for the antitumor activity of these compounds. In the beginning of Year 3, more potent analogs were synthesized in accordance with what was learned from previous structure activity relationship (SAR) analysis. Biological results indicate our indole drug candidates exhibit excellent growth inhibitory activity in both estrogen dependent and estrogen independent human breast cancer cell lines. They also possess high potency against tamoxifen resistant human breast cancer cells and display no undesired estrogenic side effects in human Ishikawa endometrial adenocarcinoma cells. Two of the most promising compounds were subjected to mechanistic studies in cell cultures, and their antitumor ability (both preventive and therapeutic activities) was also assessed in animal models.

In the cell culture studies of anchorage independent growth of human breast cancer cells, our lead indole analog showed much more potent chemopreventive activity than tamoxifen. In the animal studies, all compounds were administered orally, and low dose levels of our indole analogs significantly prevented the growth of estrogen induced mammary tumors. Given at a higher dose level to test their chemotherapeutic effect, our compounds eventually stopped the growth of tumors. None of the mice in the experimental groups showed adverse affects from their treatments.

In summary, we have completed all the tasks we proposed and achieved our goal of developing novel drug candidates that improve upon a naturally occurring tumor inhibitor I3C to prevent as well as treat breast cancer.

Primary prevention has the largest potential for reducing the incidence, problems, and mortality of any disease. Our cancer preventive agents also have chemotherapeutic effects, and developing them for clinical use have the potential for having a tremendous effect on reducing the impact of breast cancer in California.