Abstract
The present study showed that GDC-0941 potently sensitized breast cancer to ABT-737 in vitro and in vivo. ABT-737 exhibited limited lethality in breast cancer cells; however, when combined with GDC-0941, it displayed strong synergistic cytotoxicity and enhanced caspase-mediated apoptosis. GDC-0941 promoted proteasomal degradation of Mcl-1, of which the overexpression has been validated to confer ABT-737 resistance, thereby enhanced the anticancer efficacy of ABT-737. Furthermore, the combination of GDC-0941 and ABT-737 exerted increased anti-tumor efficacy on MDA-MB-231 xenograft models. Overall, our data described unprecedentedly the promising therapeutic potential and underlying mechanisms of combining GDC-0941 with ABT-737 in treating breast cancer.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Biphenyl Compounds / pharmacology*
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Breast Neoplasms* / drug therapy
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Breast Neoplasms* / metabolism
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Breast Neoplasms* / pathology
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Caspases / metabolism
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Cell Line, Tumor
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Drug Synergism
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Female
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Humans
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Indazoles / pharmacology*
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Mice
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Mice, Nude
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Myeloid Cell Leukemia Sequence 1 Protein
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Neoplasm Transplantation
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Nitrophenols / pharmacology*
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Sulfonamides / pharmacology*
Substances
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2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
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ABT-737
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Antineoplastic Agents
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Biphenyl Compounds
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Indazoles
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Phosphoinositide-3 Kinase Inhibitors
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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Caspases