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Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737.

Tahir SK, Yang X, Anderson MG, Morgan-Lappe SE, Sarthy AV, Chen J, Warner RB, Ng SC, Fesik SW, Elmore SW, Rosenberg SH, Tse C
Cancer Res. 2007 67 (3): 1176-83

PMID: 17283153 · DOI:10.1158/0008-5472.CAN-06-2203

ABT-737 is a novel and potent Bcl-2 antagonist with single-agent activity against small-cell lung cancer (SCLC) cell lines. Here, we evaluated the contribution of Bcl-2 family members to the in vitro cellular response of several SCLC cell lines to ABT-737. Relatively higher levels of Bcl-2, Bcl-X(L), Bim and Noxa, and lower levels of Mcl-1 characterized naïve SCLC cell lines that were sensitive to ABT-737. Conversely, a progressive decrease in the relative levels of Bcl-2 and Noxa and a progressive increase in Mcl-1 levels characterized the increased resistance of H146 cells following chronic exposure to ABT-737. Knockdown of Mcl-1 with small interfering RNA sensitized two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitized H196 cells to ABT-737. Combination treatment with DNA-damaging agents was extremely synergistic with ABT-737 and was associated with the down-regulation of Mcl-1 and the up-regulation of Noxa, Puma, and Bim in H196 cells. Thus, SCLC cells sensitive to ABT-737 expressed the target proteins Bcl-2 and Bcl-X(L), whereas Mcl-1 and factors regulating Mcl-1 function seem to contribute to the overall resistance of SCLC cells to ABT-737. Overall, these observations provide further insight as to the mechanistic bases for ABT-737 efficacy in SCLC and will be helpful for profiling patients and aiding in the rational design of combination therapies.

MeSH Terms (25)

Antineoplastic Combined Chemotherapy Protocols Apoptosis Apoptosis Regulatory Proteins Bcl-2-Like Protein 11 Biphenyl Compounds Carboplatin Carcinoma, Small Cell Cell Growth Processes Cell Line, Tumor Down-Regulation Drug Synergism Etoposide Humans Lung Neoplasms Membrane Proteins Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Proteins Nitrophenols Piperazines Proto-Oncogene Proteins Proto-Oncogene Proteins c-bcl-2 RNA, Small Interfering Sulfonamides Transfection Up-Regulation

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