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The antiapoptotic protein Bcl-2 contributes to a more chemoresistant phenotype of nonsmall cell lung cancer and therefore serves as an important target for novel anticancer strategies. Interestingly, docetaxel as a standard of care for treatment of nonsmall cell lung cancer has been shown to inactivate the Bcl-2 function by phosphorylation. We investigated the Bcl-2 expression status of nonsmall cell lung cancer cells in response to cisplatin or docetaxel and its effect on sensitizing nonsmall cell lung cancer cells by Bcl-2 downregulation employing a small interfering RNA approach. Bcl-2 expression was assessed by Western blotting and RT-PCR. Cell proliferation and apoptosis of nonsmall cell lung cancer cells were measured by an MTS-based assay and Annexin V/7-Aminoactinomycin, respectively. Combination treatment of Bcl-2 small interfering RNA with cisplatin resulted in a synergistic activity. By contrast, Bcl-2 downregulation did not sensitize nonsmall cell lung cancer cells to docetaxel. Of note, docetaxel treatment resulted in Bcl-2 phosphorylation of nonsmall cell lung cancer cells, whereas cisplatin increased the Bcl-2 overall expression and abrogated Bcl-2 phosphorylation. On the basis of our findings, a Bcl-2 silencing approach appears to be a suitable strategy for sensitizing nonsmall cell lung cancer to cisplatin, but not to docetaxel.