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dc.contributor.authorHarrison, Luke R
dc.contributor.authorMicha, Dimitra
dc.contributor.authorBrandenburg, Martin
dc.contributor.authorSimpson, Kathryn L
dc.contributor.authorMorrow, Christopher J
dc.contributor.authorDenneny, Olive
dc.contributor.authorHodgkinson, Cassandra L
dc.contributor.authorYunus, Zaira
dc.contributor.authorDempsey, Clare E
dc.contributor.authorRoberts, Darren L
dc.contributor.authorBlackhall, Fiona H
dc.contributor.authorMakin, Guy W J
dc.contributor.authorDive, Caroline
dc.date.accessioned2012-01-25T13:19:31Z
dc.date.available2012-01-25T13:19:31Z
dc.date.issued2011-03-01
dc.identifier.citationHypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1. 2011, 121 (3):1075-87 J. Clin. Invest.en
dc.identifier.issn1558-8238
dc.identifier.pmid21393866
dc.identifier.doi10.1172/JCI43505
dc.identifier.urihttp://hdl.handle.net/10541/204710
dc.description.abstractSolid tumors contain hypoxic regions in which cancer cells are often resistant to chemotherapy-induced apoptotic cell death. Therapeutic strategies that specifically target hypoxic cells and promote apoptosis are particularly appealing, as few normal tissues experience hypoxia. We have found that the compound ABT-737, a Bcl-2 homology domain 3 (BH-3) mimetic, promotes apoptotic cell death in human colorectal carcinoma and small cell lung cancer cell lines exposed to hypoxia. This hypoxic induction of apoptosis was mediated through downregulation of myeloid cell leukemia sequence 1 (Mcl-1), a Bcl-2 family protein that serves as a biomarker for ABT-737 resistance. Downregulation of Mcl-1 in hypoxia was independent of hypoxia-inducible factor 1 (HIF-1) activity and was consistent with decreased global protein translation. In addition, ABT-737 induced apoptosis deep within tumor spheroids, consistent with an optimal hypoxic oxygen tension being necessary to promote ABT-737–induced cell death. Tumor xenografts in ABT-737–treated mice also displayed significantly more apoptotic cells within hypoxic regions relative to normoxic regions. Synergies between ABT-737 and other cytotoxic drugs were maintained in hypoxia, suggesting that this drug may be useful in combination with chemotherapeutic agents. Taken together, these findings suggest that Mcl-1–sparing BH-3 mimetics may induce apoptosis in hypoxic tumor cells that are resistant to other chemotherapeutic agents and may have a role in combinatorial chemotherapeutic regimens for treatment of solid tumors.
dc.language.isoenen
dc.subject.meshAnimals
dc.subject.meshAnoxia
dc.subject.meshApoptosis
dc.subject.meshBiphenyl Compounds
dc.subject.meshCell Line, Tumor
dc.subject.meshDown-Regulation
dc.subject.meshDrug Resistance, Neoplasm
dc.subject.meshDrug Screening Assays, Antitumor
dc.subject.meshHumans
dc.subject.meshInhibitory Concentration 50
dc.subject.meshMale
dc.subject.meshMice
dc.subject.meshNeoplasm Transplantation
dc.subject.meshNeoplasms
dc.subject.meshNitrophenols
dc.subject.meshPeptide Fragments
dc.subject.meshPiperazines
dc.subject.meshProto-Oncogene Proteins
dc.subject.meshProto-Oncogene Proteins c-bcl-2
dc.subject.meshSulfonamides
dc.titleHypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1.en
dc.typeArticleen
dc.contributor.departmentClinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, United Kingdom.en
dc.identifier.journalJournal of Clinical Investigationen
html.description.abstractSolid tumors contain hypoxic regions in which cancer cells are often resistant to chemotherapy-induced apoptotic cell death. Therapeutic strategies that specifically target hypoxic cells and promote apoptosis are particularly appealing, as few normal tissues experience hypoxia. We have found that the compound ABT-737, a Bcl-2 homology domain 3 (BH-3) mimetic, promotes apoptotic cell death in human colorectal carcinoma and small cell lung cancer cell lines exposed to hypoxia. This hypoxic induction of apoptosis was mediated through downregulation of myeloid cell leukemia sequence 1 (Mcl-1), a Bcl-2 family protein that serves as a biomarker for ABT-737 resistance. Downregulation of Mcl-1 in hypoxia was independent of hypoxia-inducible factor 1 (HIF-1) activity and was consistent with decreased global protein translation. In addition, ABT-737 induced apoptosis deep within tumor spheroids, consistent with an optimal hypoxic oxygen tension being necessary to promote ABT-737–induced cell death. Tumor xenografts in ABT-737–treated mice also displayed significantly more apoptotic cells within hypoxic regions relative to normoxic regions. Synergies between ABT-737 and other cytotoxic drugs were maintained in hypoxia, suggesting that this drug may be useful in combination with chemotherapeutic agents. Taken together, these findings suggest that Mcl-1–sparing BH-3 mimetics may induce apoptosis in hypoxic tumor cells that are resistant to other chemotherapeutic agents and may have a role in combinatorial chemotherapeutic regimens for treatment of solid tumors.


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