Bcl-2 downregulation sensitizes nonsmall cell lung cancer cells to cisplatin, but not to docetaxel.
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.
Losert
Doris
D
Department of Clinical Pharmacology, Section of Experimental Oncology/Molecular Pharmacology, Medical University Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Pratscher
Barbara
B
Soutschek
Jürgen
J
Geick
Anke
A
Vornlocher
Hans-Peter
HP
Müller
Markus
M
Wacheck
Volker
V
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation; D002945:Cisplatin / Q000494:pharmacology*; D000077143:Docetaxel; D015536:Down-Regulation; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043823:Taxoids / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin