Abstract
In HeLa cells the combinatorial knockdown of Bcl-xL and Mcl-1 is sufficient to induce spontaneous apoptosis. Quinoxaline derivatives were screened for the induction of Mcl-1 dependent apoptosis using a cell line without functional Bcl-xL. Quinoxaline urea analog 1 h was able to specifically induce apoptosis in an Mcl-1 dependent manner. We demonstrate that even small changes to 1h results in dramatic loss of activity. In addition, 1 h and ABT-737 synergistically inhibit cell growth and induce apoptosis. Our results also suggest that 1h could have therapeutic potential against ABT-737 refractory cancer.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects
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Biphenyl Compounds / pharmacology
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HeLa Cells
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Humans
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols / pharmacology
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Quinoxalines / chemical synthesis
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Quinoxalines / chemistry*
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Quinoxalines / pharmacology
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Structure-Activity Relationship
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Sulfonamides / pharmacology
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / genetics
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bcl-X Protein / metabolism
Substances
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ABT-737
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Biphenyl Compounds
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Quinoxalines
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Sulfonamides
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bcl-X Protein