Capsaicin and small cell lung cancer therapy

项目总结 辣椒素是辣椒中辛辣的成分。传统上，辣椒素被用作止痛剂。 非处方药止痛膏和乳液中的试剂。我们的研究数据首次显示， 辣椒素可诱导人小细胞肺癌(SCLC)细胞凋亡。然而，中国的发展 辣椒素作为一种可行的抗癌药物，其生物半衰期低，副作用令人不快，包括 肠痛、痛觉过敏、胃痉挛和恶心。生化研究表明，辣椒素类似物 在其C-末端区域含有长链不饱和脂肪酸(称为N-AVAM)是无味和 具有止痛活性。随后，我们检测了精选的N-AVAM的抗肿瘤活性 辣椒素。我们观察到，无刺激性的N-AVAM辣椒素类似物Arvanil表现出更强的促进作用。 人小细胞肺癌中与辣椒素相关的凋亡活性。然而，芳香胺是一种粘度很大的液体，溶解性很差。 属性。基于Arvanil的结构主题，目前的R15更新申请提出了结构- 活性关系(SAR)研究，以确定具有改善的生物利用度和抗肿瘤作用的辣椒素类似物 肿瘤活性和人小细胞肺癌。此外，Arvanil使耐铂的人SCLCs敏化 伊立替康诱导细胞凋亡。阿凡尼对人体的增敏活性大于辣椒素。 SCLC。使用这些观察结果作为概念验证，当前的续订申请将测试 一组非刺激性N-AVAM辣椒素类似物的化学增敏能力。我们的核心假设是 续期申请是，特区的研究将导致鉴定辣椒素类化合物，这将 在体内作为单一药物和与伊立替康联合使用显示出强大的抗肿瘤活性。此外, 我们的目标是研究这些N-AVAM辣椒素化合物在小鼠模型中的生物利用度。创新的 我们申请资助的特点是，我们的目标是测试其抗肿瘤活性和化学增敏活性。 这些辣椒素类似物在人小细胞肺癌的PDX模型中。我们建议书中概述的实验模型 为本科生和研究生提供有意义的研究经验。我们的研究结果 将为经典和耐铂的小细胞肺癌带来新疗法的希望。

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.