Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1

• Published in: The Journal of clinical investigation 2011-03, Vol.121 (3), p.1075-1087
• Main Authors: Harrison, Luke R E, Micha, Dimitra, Brandenburg, Martin, Simpson, Kathryn L, Morrow, Christopher J, Denneny, Olive, Hodgkinson, Cassandra, Yunus, Zaira, Dempsey, Clare, Roberts, Darren, Blackhall, Fiona, Makin, Guy, Dive, Caroline
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biomarkers; Biomedical research; Biphenyl Compounds - pharmacology; Cancer cells; Cancer therapies; Cell death; Cell Line, Tumor; Cellular proteins; Chemotherapy; Cytotoxicity; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Humans; Hypoxia; Inhibitory Concentration 50; Leukemia; Lung cancer; Male; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; Neoplasms - drug therapy; Neoplasms - pathology; Nitrophenols - pharmacology; Peptide Fragments - metabolism; Physiological aspects; Piperazines - pharmacology; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Sulfonamides - pharmacology; Tumors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci43505

Solid 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.