Discovery of cell cycle inhibitors from natural products
DESCRIPTION (provided by applicant): The need for new and effective chemotherapeutic agents that selectively target cancer cells and thus, would have a much higher therapeutic index is urgent. Most chemotherapeutic agents damage normal dividing cells which accounts for the majority of the side effects of these drugs. The discovery and development of cancer selective chemotherapy is a principal goal of the National Cancer Institute. During Phase 1, this project we identified symlubricol A, a cancer selective compound isolated from a mushroom. This compound is similar in potency to our positive control, camptothecin. Remarkably, it was also more than 3-fold selective for cancer cell toxicity (ED50 MFC-7/ED50 MCF10A = 3.71) in an assay that doxorubicin was 5-fold selective for proliferating noncancerous cells toxicity (ED50 MFC-7/ED50 MCF10A = 0.16). During Phase 2, we will characterize this compound in 1), cell cycle inhibition studies, 2), in vivo mouse tumor models and 3), the NCI 60 cell line toxicity panel. If the results justify additional development, we will continue this development either through strategic partnerships or in collaboration with the NCI. To discover additional selective and potent anticancer agents, we will continue screening LifePharms' unique and proprietary library of extracts from >13,000 field collected basidiomycetes and ascomycetes (mushrooms) for inhibitors that selectively target the cell cycle events in cancer cells. Natural products have been a particularly good source of compounds that are excellent probes for targets vital to the cell cycle. We propose to screen extracts for toxicity in a panel of three cancerous cell lines, i) MFC-7, ii) NCI-H690 and iii), SF-268. Those extracts with potent activity (IC90 is equal to or less than 20 ug/ml) will be screened against the nontumorigenic cell lines MCF10A, to determine a selectivity quotient. Extracts containing cancer selective compounds will be fractionated and the active compound(s) isolated and identified. The stage at which they block the cell cycle will be identified and lead compounds will be examined further for activity in in vivo antitumor models and NCI 60-cell line panel. By exploiting those differences between proliferating normal and cancer cells, we expect to find additional novel chemical compounds with increased tumor selectivity and reduced toxicity.
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1084 Shennecossett Rd University Of Connecticut Groton, CT 06340
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