具有逆转多药耐药特性的新型噻吩类微管蛋白抑制剂抗乳腺癌的作用机制研究

Primary intrinsic and/or acquired multidrug resistance (MDR) is the main obstacle to successful cancer treatment. Medicine that can reverse MDR has been intensely studied. We firstly synthesized a series of 5 - aryl alkynyl substituted 2 - benzoyl thiophene compounds (PST), using a well-known tubulin polymerization inhibitor as precursor compound. Earlier studies showed that PST can not only inhibit the proliferation of variety of breast cancer cells but also have the same effect to drug-resistant strains. The further studies demonstrated that PST can block breast cancer cells in the G2 / M phase and inhibit microtubule protein polymerization. In addition, out of expectation, the expression of P-gp in drug-resistant strains decreased. With above findings, we speculate that the anti-cancer effect of PST may be a dual- target system which works both on microtubule protein polymerization and the expression of P-gp. In this project, we aim to clarify the novel compounds PST's anti-breast cancer mechanism through studying the tubulin and P-gp, using siRNA interference，immunohistochemistry , 2D DIGE , microarray , animal experiments, etc. It is certain that the results will be very helpful for the development of new drugs in the future.

肿瘤的多药耐药性一直是临床治疗的难题，逆转肿瘤多药耐药性是当前研究的热点内容。课题组在前期研究中，对微管蛋白聚合抑制剂进行结构修饰，首次合成了系列5-芳炔基取代的2-苯甲酰基噻吩类化合物（PST），实验发现PST可抑制多种乳腺癌细胞的增殖，对耐药株也有抑制作用，进一步的实验表明PST可阻滞乳腺癌细胞于G2/M期，并可抑制微管蛋白的聚合，且能降低P-gp在耐药株中的表达。我们推测PST的抗乳腺癌作用与微管蛋白相关，但确切的机制尚不清楚，此外，PST可抑制耐药蛋白的表达，说明其抗肿瘤的作用有可能是双靶点机制，即与乳腺癌耐药蛋白也相关。因此，本项目以微管蛋白和耐药蛋白P-gp为切入点，拟采用siRNA干扰、二维电泳、基因芯片、动物实验等方法围绕PST对肿瘤微管蛋白的影响、P-gp蛋白的影响及其他耐药蛋白和耐药基因的影响等方面开展研究，试图阐明新型化合物PST的抗乳腺癌的双重作用机制。

课题组在前期研究中， 对微管蛋白聚合抑制剂进行结构修饰，首次合成了系列 5-芳炔基取代的 2-苯甲酰基噻吩类化合物（PST），实验发现 PST 可抑制多种乳腺癌细胞的增殖，对耐药株也有抑制作用，进一步的实验表明 PST 可阻滞乳腺癌细胞于 G2/M 期，并可抑制微管蛋白的聚合，且能降低 P-gp 在耐药株中的表达。在后续的实验中，我们选取了活性最好的PST-3，探究其对乳腺癌化疗耐药的影响。实验结果表明，PST-3可以增加乳腺癌细胞对多柔比星的敏感性，其具体制剂可能是通过影响PTEN的水平。本研究的结果对于实现乳腺癌患者的个体化化疗，提高乳腺癌患者的化疗效果具有一定的指导意义。