Rapamycin potentiates cytotoxicity by docetaxel possibly through downregulation of Survivin in lung cancer cells

Lung cancer cells were treated with docetaxel and rapamycin. The effect on the proliferation of lung cancer cells was evaluated using the MTT method, and cell apoptosis was measured by flow cytometry. Protein expression and level of phosphorylation were assayed using Western Blot method.Co-treatment of rapamycin and docetaxel was found to favorably enhance the cytotoxic effect of docetaxel in four lung cancer cell lines. This tumoricidal boost is associated with a reduction in the expression and phosphorylation levels of Survivin and ERK1/2, respectively.The combined application of mTOR inhibitor and docetaxel led to a greater degree of cancer cell killing than that by either compound used alone. Therefore, this combination warrants further investigation in its suitability of serving as a novel therapeutic scheme for treating advanced and recurrent lung cancer patients.Despite recent advancement in the multidisciplinary treatment of cancer, the prognosis for lung cancer remains poor in more advanced stages and recurrent cases. According to World Health Organization, lung cancer ranks at the top in cancer-related mortalities in humans, killing more than one million people each year.Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase of 289 kDa, is critically involved in cellular signal transduction mediated by phosphatidylinositol 3 kinase (PI3K)[1]. The activation of mTOR results in changes in multiple cellular processes, e.g., catabolism, anabolism, proliferation, growth and apoptosis[2,3]. Although mTOR is expressed in virtually all mammalian cells, it is believed to play a particularly important role in cancer cells[4-7]. Recent reports have suggested that PI3K/Akt/mTOR pathway is often activated in various forms of lung cancer and that this pathway is considered to be important for cancer cells' survival, proliferation, angiogenesis and resistance to chemotherapy. This pathway can, therefore, be regarded as an attractive target of molecular t