Capsaicin and small cell lung cancer therapy

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PROJECT SUMMARY Capsaicin is the spicy, pungent ingredient of chili peppers. Conventionally, capsaicin is used as a pain-relieving agent in over-the-counter analgesic creams and lotions. Our research data showed for the first time that capsaicin triggered apoptosis in human small cell lung cancers (SCLCs). However, the development of capsaicin as a feasible anti-cancer drug is limited by its low biological half-life, unpleasant side effects including gut pain, hyperalgesia, stomach cramps and nausea. Biochemical studies have shown that capsaicin analogs containing long chain unsaturated fatty acids in its C-terminal region (called N-AVAMs) were non-pungent and possessed pain-relieving activity. Subsequently, we examined the anti-tumor activity of selected N-AVAM capsaicinoids. We observed that the non-pungent N-AVAM capsaicin analog arvanil displayed greater pro- apoptotic activity relative to capsaicin in human SCLCs. However, arvanil is a viscous liquid with poor solubility properties. Based on the structural motifs of arvanil, the present R15 renewal application proposes structure- activity relationship (SAR) studies to identify capsaicin analogs with improved bioavailability properties and anti- tumor activity and in human SCLCs. Furthermore, arvanil sensitized platinum-resistant human SCLCs to irinotecan-induced apoptosis. The chemosensitization activity of arvanil was greater than capsaicin in human SCLCs. Using these observations as proof-of-concept, the current renewal application will test the chemosensitization ability of a panel of non-pungent N-AVAM capsaicin analogs. The central hypothesis of our renewal application is that the SAR studies will lead to the identification of capsaicinoids which, will display robust anti-tumor activity as single agents and in combination with irinotecan in vivo. In addition, we aim to investigate the bioavailability of these N-AVAM capsaicin compounds in mice models. An innovative feature of our grant application is that we aim to test the anti-tumor activity and chemosensitization activity of these capsaicin analogs in PDX models of human SCLCs. The experimental models outlined in our proposal provide meaningful research experiences for undergraduate and graduate students. The results of our studies will foster the hope of novel therapies in classical and platinum-resistant SCLCs.