磷脂酰肌醇3激酶抑制剂XJM002抗雄激素非依赖性前列腺癌的作用及机制的研究

It is difficult to treat androgen-independent prostate cancer (AIPC). Research indicates that elevated signaling of the phosphoinositide-3 kinase (PI3K) pathway is the critical factor for androgen-independent growth of AIPC cells. Disruption of the PI3K singlaing pathway leads to AIPC cell apoptosis, suggesting that PI3K is a promising therapeutic target for this type of cancer. Recently, we identified a nove small molecule compoundXJM002 which potently inhibits PI3K activity and restrains the progression of AIPC cells. The proliferation of the AIPC cell lines PC3 and DU145 were markedly suppressed by XJM002. However, the mechanisms are yet to define. In the present proposal, we will exentively investigate the detailed mechanisms in cell-free, cell and animal levels and specifically aims: (1) To elucidate the inhibition manner of XJM002 on PI3 kinases; (2) to investigate the mechnism of the XJM002 regulating PI3K/Akt/mTOR pathway; 3) to clarify the impact of the XJM002 on autophage; 4) to understand whether XJM002 suppressed the AIPC tumor growth in vivo is via the PI3K pathway. The results will form a solid raionale to develop XJM002 as a promising anti-AIPC drug.

激素非依赖性前列腺癌(AIPC)是目前前列腺癌治疗的难点。研究发现磷脂酰肌醇-3-激酶（PI3K）信号途径是AIPC在去势条件下得以存活和增殖的关键环节。我们在前期工作发现小分子化合物XJM002能通过抑制PI3K活性而呈现抗AIPC的作用，但机制不明。本项目拟在前期工作基础上从细胞水平阐明XJM002对AIPC细胞I、II、III型PI3K激酶的抑制作用及酶动力学参数，研究XJM002对PI3K/Akt/mTOR信号通路及mTOR复合物组分的调控作用，分析其对自噬活性的影响，并在前列腺癌动物模型中进一步明确XJM002对AIPC的抑制作用及作用机制。该项目可以从分子和整体水平明确XJM002抗AIPC的作用机制，为XJM002开发成具有自主知识产权的抗癌药物奠定必要的基础，以加快临床抗AIPC新药的研发。

激素非依赖性前列腺癌是目前前列腺癌治疗的难点，但是最近的研究表明PI3K/Akt信号通路与前列腺癌的治疗密切相关。本项目研究了XJM002（BENC-511）对PI3K/Akt/mTOR信号通路及mTOR复合物组分的调控作用。我们分别处理了PC3细胞（PTEN缺失型前列腺癌细胞株）及DU145细胞（PTEN表达型前列腺癌细胞株），发现PC3细胞对BENC-511的敏感性更强，表现为细胞增殖受阻、凋亡及自噬活性增强，而给予外源性PTEN表达后，BENC-511的诱导凋亡作用则被减弱。同时，荷瘤小鼠的在体实验也表明BENC-511具有良好的抗前列腺癌作用，能够显著抑制肿瘤的生长，并促进了凋亡信号PARP的剪切激活。上述研究结果表明BENC-511具有良好的抗前列腺癌作用，并且该作用与PI3K信号通路密切相关。