ArticleThe Journal of clinical investigation2011
Hypoxic human cancer cells are sensitized to BH-3 mimetic–induced apoptosis via downregulation of the Bcl-2 protein Mcl-1.
Article in The Journal of clinical investigation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
29 citing papers in PubMed, 50 citations in OpenAlex.
- Functional Role of NOXA in Hypoxia-Mediated PD-L1 Inhibitor Response in Hepatocellular Carcinoma.International journal of molecular sciences · 2025Article
- Synergistic cytotoxicity of perifosine and ABT-737 to colon cancer cells.Journal of cellular and molecular medicine · 2023Article
- Bcl-2/Bcl-xL inhibitor ABT-263 overcomes hypoxia-driven radioresistence and improves radiotherapy.Cell death & disease · 2021Article
- Pathophysiological implications of hypoxia in human diseases.Journal of biomedical science · 2020Review
- Signaling in and out: long-noncoding RNAs in tumor hypoxia.Journal of biomedical science · 2020Review
- Article
- Targeted apoptosis of myofibroblasts with the BH3 mimetic ABT-263 reverses established fibrosis.Science translational medicine · 2017Article
- Long non-coding RNA and tumor hypoxia: new players ushered toward an old arena.Journal of biomedical science · 2017Review
- Antitumor effects of cyclin dependent kinase 9 inhibition in esophageal adenocarcinoma.Oncotarget · 2017Article
- Cancer stem cell niche models and contribution by mesenchymal stroma/stem cells.Molecular cancer · 2017Review
- VHL-deficient renal cancer cells gain resistance to mitochondria-activating apoptosis inducers by activating AKT through the IGF1R-PI3K pathway.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Article
- Pro-survival responses to the dual inhibition of anti-apoptotic Bcl-2 family proteins and mTOR-mediated signaling in hypoxic colorectal carcinoma cells.BMC cancer · 2016Article
- Down-regulation of miR-320 associated with cancer progression and cell apoptosis via targeting Mcl-1 in cervical cancer.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2016Article
- Cell Death Conversion under Hypoxic Condition in Tumor Development and Therapy.International journal of molecular sciences · 2015Review
- Rapamycin rescues ABT-737 efficacy in small cell lung cancer.Cancer research · 2014Article
- Targeting cell death signaling in colorectal cancer: current strategies and future perspectives.World journal of gastroenterology · 2014Review
- Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Article
- BMX acts downstream of PI3K to promote colorectal cancer cell survival and pathway inhibition sensitizes to the BH3 mimetic ABT-737.Neoplasia (New York, N.Y.) · 2014Article
- Hypoxia modulates the activity of a series of clinically approved tyrosine kinase inhibitors.British journal of pharmacology · 2014Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.