Mode of Action of the Amaryllidaceae Alkaloid Lycorine-Promising Anticancer Agent

描述（由申请人提供）：该项目的最终目标是开发一种新的治疗策略，用于利用生物碱石蒜碱对细胞凋亡抗性癌症的独特抗增殖作用治疗癌症。虽然有很大一 大多数现有的癌症药物通过诱导肿瘤细胞的凋亡来显示其作用，许多类型的癌症，例如神经胶质瘤、黑素瘤、NSCLC等，对促凋亡刺激具有抗性，并且通常与令人沮丧的癌症有关。因此，迫切需要显示针对此类抗肿瘤抗性癌症的抗增殖作用和/或抑制肿瘤转移扩散的新化学型。在初步工作中，PI的合作化学生物学/药物发现团队已经表明，生物碱石蒜碱修改癌细胞中的肌动蛋白细胞骨架组织，并损害其增殖和迁移。石蒜碱对抗肿瘤和敏感细胞系都发挥这些作用，使癌细胞对促凋亡剂敏感，并显示出比正常细胞高15倍的抗癌效力。此外，石蒜碱在B16 F10小鼠黑色素瘤模型中显示出显著的体内治疗益处，该模型由原位脑移植的黑色素瘤细胞组成。这些初步结果形成了一个令人信服的情况下，石蒜碱的作用模式在癌细胞中的一个彻底的了解和利用这一知识的发展新的战略，以治疗癌症与令人沮丧的肿瘤。拟议的工作涉及石蒜碱-炔探针的制备，其将针对一组抗增殖癌细胞进行评估，目的是鉴定保留石蒜碱的抗增殖效力和作用模式的衍生物。然后将合适的炔探针用于蛋白质下拉测定，目的在于靶蛋白质鉴定。几个备份目标识别和目标验证策略也被提出来确认这种创新的化疗方法。

DESCRIPTION (provided by applicant): The ultimate goal of this project is the development of a novel therapeutic strategy for the treatment of cancer capitalizing on the unique antiproliferative effects of the alkaloid lycorine on apoptosis resistant cancers. Although a large majority of current cancer drugs exhibit their effects through the induction of apoptosis in tumor cells, many types of cancer, such as glioma, melanoma, NSCLC, among others, are resistant to proapoptotic stimuli and are typically associated with dismal prognoses. Therefore, new chemotypes that display antiproliferative effects against such apoptosis-resistant cancers and/or inhibit tumor metastatic spread are urgently needed. In preliminary work, the PI's collaborative chemical biology/drug discovery team has shown that the alkaloid lycorine modifies actin cytoskeleton organization in cancer cells, and impairs both their proliferation and migration. Lycorine exerts these effects with both apoptotic-resistant and susceptible cell lines, sensitizes cancer cells to proapoptotic agents, and displays 15 times greater potency toward cancer versus normal cells. Furthermore, lycorine showed significant therapeutic benefit in vivo in the B16F10 mouse melanoma model, consisting of orthotopically brain-grafted melanoma cells. These preliminary results form a compelling case for a thorough understanding of lycorine's mode of action in cancer cells and utilization of this knowledge for the development of novel strategies to treat cancers with dismal prognoses. The proposed work involves the preparation of lycorine- alkyne probes, which will be evaluated against a panel of apoptosis-resistant cancer cells with the goal of identifying derivatives retaining the antiproliferative potency and mode of action of lycorine. Suitable alkyne probes will then be used in protein pull-down assays, aimed at target protein identification. Several back-up target identification and target validation strategies are also proposed to confirm this innovative chemotherapeutic approach.