E. Mahdavian, B. Salvatore, J. Clifford
May 1, 2007
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Cancer Research
Abstract
3975 Fusarochromanone (FC-101a) is a flavinoid produced by the mold, Fusarium equiseti. FC-101a induces tibial dyschondroplasia in young chickens. This activity is the result of powerful anti-angiogenic activity, whereby mold growing on chicken feed produces FC-101a, which inhibits the growth of blood vessels in the developing bones of broiler chicks. FC-101a has an IC50 of 50 nM against human microvascular endothelial cells. Thus it could be a potent anti-angiogenic agent in man as well. It was later discovered that FC-101a also acts directly on cancer cells. The molecule9s anti-cancer potency is best demonstrated by IC50 values of less than 10 nM against both human melanoma and small cell lung cancer in vitro for the induction of apoptosis. Thus, we viewed FC-101a to be an excellent lead candidate for the discovery of new therapeutic agents. Further development of this lead compound as a drug requires that we undertake its total synthesis and a set of new FC-101a analogs that possess similar in vitro activity, but also manifest greater activity in vivo. Our research group has synthesized a number of novel analogs of FC101a and conducted a series of preliminary assays to determine the effect of these analogs on cell viability. We have analyzed human skin squamous cell carcinoma (SCC) cells (SRB12-p9 cell line) and a clone of SRB12-p9 cells that has been stably transfected with a dominant-negative acting form of Stat3 (p9 dn5), human keratinocyte-derived cells (HaCaT cell line), and human breast carcinoma cells (MDA-MB-231 cell line). Surprisingly, most of the FC101a analogs caused an increase in cell viability for all cell lines as determined by the MTT cell viability assay, compared to untreated controls. A time course of treatment of HaCaT cells with 10_M of FC101a analogs further confirmed the positive effect on cell viability. For the seven analogs tested we observed a time dependent increase in cell number for up to 4 days, ranging from 29.8% to 66.7%. Experiments are in progress to determine the mechanism of the enhanced cell viability effect. Fluorescence activated cell sorting (FACS) analysis and apoptosis assays are underway to determine the relative contribution of increased proliferation and/or decreased cell death to the enhanced cell numbers observed for treated cells. In addition, we are exploring the potential anti-angiogenic effect of the analogs.