Zou Zu-Quan, Zhang Xiao-Hong, Wang Feng, Shen Qi-Jun, Xu Jin, Zhang Li-Na, Xing Wen-Hua, Zhuo Ren-Jie, Li Duo
Department of Food Science and Nutrition, Zhejiang University, Hangzhou, PR China.
Int J Mol Med. 2009 Jul;24(1):97-101. doi: 10.3892/ijmm_00000212.
PI-103, the first synthetic multitargeted compound which simultaneously inhibits PI3Kalpha and mammalian target of rapamycin (mTOR) shows high antitumor activity in glioma xenografts. In the present study, clear antitumor activity was observed with PI-103 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460, by simultaneously inhibiting p70s6k phosporylation and Akt phosphorylation in response to mTOR inhibition. In addition, H460 cells with activating mutations of PIK3CA were more sensitive to PI-103 than A549 cells with wild-type PIK3CA. PI-103 was found to inhibit growth by causing G0-G1 arrest in A549 and H460 cells. Western blotting showed that PI-103 induced down-regulation of cyclin D1 and E1 and simultaneously up-regulated p21 and p27, associated with arrest in the G0-G1 phase of the cell cycle. Furthermore, p53, the tumor suppressor which transcriptionally regulates p21, was also upregulated with PI-103 treatment. Collectively, our results suggest that multitargeted intervention is the most effective tumor therapy, and the cooperative blockade of PI3Kalpha and mTOR with PI-103 shows promise for treating gefitinib-resistant NSCLC.
PI-103是首个同时抑制PI3Kα和雷帕霉素哺乳动物靶点（mTOR）的合成多靶点化合物，在胶质瘤异种移植模型中显示出高抗肿瘤活性。在本研究中，在两种吉非替尼耐药的非小细胞肺癌（NSCLC）细胞系A549和H460中，通过同时抑制p70s6k磷酸化和对mTOR抑制产生反应的Akt磷酸化，观察到PI-103治疗具有明显的抗肿瘤活性。此外，具有PIK3CA激活突变的H460细胞比具有野生型PIK3CA的A549细胞对PI-103更敏感。发现PI-103通过使A549和H460细胞发生G0-G1期阻滞来抑制生长。蛋白质印迹法显示，PI-103诱导细胞周期蛋白D1和E1下调，同时上调p21和p27，这与细胞周期G0-G1期阻滞相关。此外，PI-103治疗还上调了转录调控p21的肿瘤抑制因子p53。总体而言，我们的结果表明多靶点干预是最有效的肿瘤治疗方法，并且PI-103对PI3Kα和mTOR的协同阻断在治疗吉非替尼耐药的NSCLC方面显示出前景。
