Wangpaichitr Medhi, Wu Chunjing, You Min, Kuo M T, Feun Lynn, Lampidis Theodore, Savaraj Niramol
Department of Molecular Cell and Developmental Biology, University of Miami School of Medicine, Miami, FL, USA.
Eur J Pharmacol. 2008 Sep 4;591(1-3):124-7. doi: 10.1016/j.ejphar.2008.06.028. Epub 2008 Jun 12.
We show that cisplatin resistance in certain lung cancer cell lines can be reversed through inhibition of mTOR (mammalian Target of Rapamycin). These cell lines appear to possess high levels of phospho-mTOR, phospho-AKT and other growth-related proteins, such as hTERT (human telomerase reverse transcriptase), and Cyclin D3 which decrease upon inhibition of mTOR. Interestingly in one cisplatin resistant cell line which expresses BCL2/BCLxL, treatment with mTOR inhibitor (CCI-779) results in decreased levels of these anti-apoptotic proteins and may contribute to increasing apoptosis. Moreover, continuous exposure to CCI-779 was found to increase the expression of the multi-drug resistant P-gp1(P-gycoprotein1) efflux pump and therefore should be taken into consideration when designing clinical trials with this compound.
我们发现，通过抑制mTOR（哺乳动物雷帕霉素靶蛋白），某些肺癌细胞系中的顺铂耐药性可以被逆转。这些细胞系似乎具有高水平的磷酸化mTOR、磷酸化AKT以及其他与生长相关的蛋白质，如hTERT（人端粒酶逆转录酶）和细胞周期蛋白D3，而在抑制mTOR后这些蛋白水平会降低。有趣的是，在一种表达BCL2/BCLxL的顺铂耐药细胞系中，用mTOR抑制剂（CCI-779）处理会导致这些抗凋亡蛋白水平降低，这可能有助于增加细胞凋亡。此外，发现持续暴露于CCI-779会增加多药耐药性P-gp1（P-糖蛋白1）外排泵的表达，因此在设计使用该化合物的临床试验时应予以考虑。
