Taccalonolides: Mechanisms of Action and Cellular Resistance

描述（由申请人提供）：微管稳定剂是用于治疗癌症的重要药物。该项目的重点是一类新的植物来源的微管稳定剂，taccalonolides。他卡内酯具有独特的作用机制。他们是第一个微管稳定剂确定有紫杉醇样作用的细胞，但他们不结合微管蛋白。全面的研究，以确定细胞的作用机制和耐药性的taccalonolides。这些研究有望确定稳定微管的新靶点，从而产生抗肿瘤作用。从这些研究中获得的信息也将确定由化学和生物多样性微管稳定剂引发的信号通路，以启动有丝分裂停滞和随后的凋亡。预计这将导致识别新的癌症治疗靶点。这些靶点可以提供紫杉烷类的抗癌功效以及规避紫杉烷类药物耐药性和微管蛋白相关毒性的能力。这项工作的第一个目标是确定taccalonolides的细胞结合位点。我们将测试的假设，taccalonolides绑定和抑制内在的细胞微管不稳定因素，导致微管稳定。第二个目标是阐明taccalonolides中断有丝分裂信号传导导致有丝分裂停滞和细胞凋亡的机制。我们将检验taccalonolides抑制Aurora A表达和活性的假设。耐药性是癌症治疗中的一个严重问题。我们将确定细胞对他卡内酯耐药的性质，并检验这些化合物可以规避导致临床紫杉烷耐药的耐药机制的假设。将测试他卡内酯绕过由于P-糖蛋白表达、微管蛋白改变和PXR介导的耐药性引起的耐药性的能力。将评价通过他卡隆暴露产生的细胞系，以确定获得性他卡隆耐药的机制。最终的目标是确定taccalonolides作用机制和耐药性的结构基础。将确定对最佳细胞毒性功效和效价、抗有丝分裂作用和抗肿瘤活性重要的特定化学成分。

DESCRIPTION (provided by applicant): Microtubule stabilizing agents are important drugs used in the treatment of cancer. The focus of this project is a new class of plant-derived microtubule stabilizers, the taccalonolides. The taccalonolides have a unique mechanism of action. They are the first microtubule stabilizers identified that have Taxol-like effects in cells but they do not bind to tubulin. Comprehensive studies are presented to identify the cellular mechanisms of action and resistance of the taccalonolides. These studies are expected to identify new targets for stabilizing microtubules that can lead to antitumor effects. Information gained from these studies will also identify the signaling pathways invoked by chemically and biologically diverse microtubule stabilizers to initiate mitotic arrest and subsequent apoptosis. This is expected to lead to the identification of new therapeutic targets for cancer. These targets could provide the anticancer efficacy of the taxanes and the ability to circumvent taxane drug resistance and tubulin-related toxicity. The first goal of this effort is to identify the cellular binding site of the taccalonolides. We will test the hypothesis that the taccalonolides bind and inhibit an intrinsic cellular microtubule destabilizing factor resulting in microtubule stabilization. A second goal is to elucidate the mechanisms by which the taccalonolides interrupt mitotic signaling leading to mitotic arrest and apoptosis. We will test the hypothesis that the taccalonolides inhibit Aurora A expression and activity. Drug resistance is a serious problem in the treatment of cancer. We will identify the nature of cellular resistance to the taccalonolides and test the hypothesis that these compounds can circumvent resistance mechanisms that contribute to taxane resistance in the clinic. The ability of the taccalonolides to bypass resistance due to P-glycoprotein expression, tubulin alterations and PXR-mediated resistance will be tested. Cell lines generated by taccalonolide exposure will be evaluated to identify the mechanisms of acquired taccalonolide resistance. The final aim will identify the structural basis for the taccalonolides mechanisms of action and resistance. Specific chemical constituents important for optimal cytotoxic efficacy and potency, antimitotic actions and antitumor activities will be determined.