Abstract
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
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Antineoplastic Combined Chemotherapy Protocols / pharmacology
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / genetics
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Bcl-2-Like Protein 11
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Biphenyl Compounds / administration & dosage
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Biphenyl Compounds / pharmacology*
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Carboplatin / administration & dosage
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Carcinoma, Small Cell / drug therapy*
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Carcinoma, Small Cell / metabolism*
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Carcinoma, Small Cell / pathology
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Cell Growth Processes / drug effects
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Cell Line, Tumor
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Down-Regulation
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Drug Synergism
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Etoposide / administration & dosage
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Membrane Proteins / biosynthesis
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Membrane Proteins / genetics
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Nitrophenols / administration & dosage
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Nitrophenols / pharmacology*
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Piperazines / administration & dosage
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Piperazines / pharmacology
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / genetics
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RNA, Small Interfering / genetics
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology*
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Transfection
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Up-Regulation
Substances
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ABT-737
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Apoptosis Regulatory Proteins
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BBC3 protein, human
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Biphenyl Compounds
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Membrane Proteins
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Proteins
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Nitrophenols
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PMAIP1 protein, human
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Piperazines
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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Sulfonamides
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Etoposide
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Carboplatin