Capsaicin and Small cell Lung Cancer Therapy

描述（申请人提供）：小细胞肺癌（SCLC）的特点是生长速度快、扩散快、早期转移和生存率低。虽然化疗最初在SCLC患者中效果良好，但他们很快就会复发并对化疗无反应。我们发表的数据表明，辣椒素（辣椒的辛辣成分）在一组人SCLC细胞系中显示出抗增殖活性，在CAM和 在无胸腺小鼠模型中。我们还观察到辣椒素的抗增殖活性是由离子通道受体的瞬时受体电位香草酸（TRPV）家族介导的。通过饮食方法给无胸腺小鼠施用辣椒素不会引起小鼠不适或毒性。此外，低浓度的辣椒素可以使人SCLC细胞对顺铂的体外生长抑制作用敏感。目前的建议将研究辣椒素和顺铂在人类小细胞肺癌肿瘤异种移植到无胸腺小鼠中的协同作用。该建议的中心假设是辣椒素将使SCLC细胞对无胸腺小鼠模型中化疗药物诱导的凋亡敏感。我们还推测SCLC的抗增殖活性是通过TRPV受体亚型介导的。此外，我们打算测量辣椒素在小鼠中的口服生物利用度和组织分布。目前资助的研究将导致在人类SCLC中识别新的基于辣椒素的联合疗法。 公共卫生相关性：小细胞肺癌（SCLC）是一种致命的恶性肿瘤，其特征是快速倍增时间和非常低的五年生存率。虽然SCLC肿瘤最初对化疗有反应，但它们经常复发，然后肿瘤变得对化疗不敏感。目前的研究表明，营养剂辣椒素可能与化疗药物一起用于治疗SCLC的联合治疗。

DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) is characterized by a high rate of growth, rapid dissemination, early metastasis and a dismal survival rate. Although chemotherapy works well initially in SCLC patients, they soon relapse and become unresponsive to chemotherapy. Our published data show that capsaicin (the spicy ingredient of chili peppers) displays anti-proliferative activity in a panel of human SCLC cell lines, in CAM and in athymic mice models. We also observed that the anti-proliferative activity of capsaicin is mediated by the transient receptor potential vanilloid (TRPV) family of ion channel receptors. The administration of capsaicin to athymic mice via dietary methods produced no discomfort or toxicity in mice. Furthermore, low concentrations of capsaicin could sensitize human SCLC cells to the growth-inhibitory effects of cisplatin in vitro. The present proposal will examine the co-operative effects of capsaicin and cisplatin in human SCLC tumors xenotransplanted into athymic mice. The central hypothesis of this proposal is that capsaicin will sensitize SCLC cells to apoptosis induced by chemotherapeutic drugs in athymic mice models. We also conjecture that the anti-proliferative activity of SCLCs is mediated via the TRPV receptor-subtypes. In addition, we intend to measure the oral bioavailability and tissue-distribution of capsaicin in mice. The studies in the present grant will lead to the identification of novel capsaicin-based combination therapies in human SCLCs. PUBLIC HEALTH RELEVANCE: Small cell lung cancer (SCLC) is a lethal malignancy characterized by rapid doubling time and very poor five-year survival rates. Although SCLC tumors are initially responsive to chemotherapy, they frequently relapse and then the tumor becomes insensitive to chemotherapy. The studies in the present grant propose that the nutritional agent capsaicin may be useful in combination therapies along with chemotherapeutic drugs for the treatment of SCLCs.