ArticleCancer research2012
Mcl-1 Phosphorylation defines ABT-737 resistance that can be overcome by increased NOXA expression in leukemic B cells.
Article in Cancer research, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 75 papers.
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Who cites it
75 citing papers in PubMed, 117 citations in OpenAlex.
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- LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers.Nature communications · 2025Article
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- Robust anti-myeloma effect of TAS0612, an RSK/AKT/S6K inhibitor, with venetoclax regardless of cytogenetic abnormalities.Leukemia · 2025Article
- Discovery of a Myeloid Cell Leukemia 1 (Mcl-1) Inhibitor That Demonstrates PotentJournal of medicinal chemistry · 2024Article
- Enhancement of the Sensitivity of the Acute Lymphoblastic Leukemia Cells to ABT-737 by Formononetin.International journal of molecular and cellular medicine · 2024Article
- Dihydroartemisinin Enhances the Therapeutic Efficacy of BH3 Mimetic Inhibitor in Acute Lymphoblastic Leukemia Cells via Inhibition of Mcl-1.Asian Pacific journal of cancer prevention : APJCP · 2024Article
- Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.The Journal of clinical investigation · 2023Article
- Combination Therapies Targeting Apoptosis in Paediatric AML:International journal of molecular sciences · 2023Article
- Progress in understanding the mechanisms of resistance to BCL-2 inhibitors.Experimental hematology & oncology · 2022Review
- High expression of B4GALT1 is associated with poor prognosis in acute myeloid leukemia.Frontiers in genetics · 2022Article
- Combination Therapy of Navitoclax with Chemotherapeutic Agents in Solid Tumors and Blood Cancer: A Review of Current Evidence.Pharmaceutics · 2021Review
- Celecoxib Analogues for Cancer Treatment: An Update on OSU-03012 and 2,5-Dimethyl-Celecoxib.Biomolecules · 2021Review
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- LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells.Cancer cell international · 2021Article
- Resistance to venetoclax and hypomethylating agents in acute myeloid leukemia.Cancer drug resistance (Alhambra, Calif.) · 2021Article
- Targeting Protein Neddylation to Inactivate Cullin-RING Ligases by Gossypol: A Lucky Hit or a New Start?Drug design, development and therapy · 2021Review
15 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
Abstract
ABT-737 is a small molecule Bcl-2 homology (BH)-3 domain mimetic that binds to the Bcl-2 family proteins Bcl-2 and Bcl-xL and is currently under investigation in the clinic. In this study, we investigated potential mechanisms of resistance to ABT-737 in leukemia cell lines. Compared with parental cells, cells that have developed acquired resistance to ABT-737 showed increased expression of Mcl-1 in addition to posttranslational modifications that facilitated both Mcl-1 stabilization and its interaction with the BH3-only protein Bim. To sensitize resistant cells, Mcl-1 was targeted by two pan-Bcl-2 family inhibitors, obatoclax and gossypol. Although gossypol was effective only in resistant cells, obatoclax induced cell death in both parental and ABT-737-resistant cells. NOXA levels were increased substantially by treatment with gossypol and its expression was critical for the gossypol response. Mechanistically, the newly generated NOXA interacted with Mcl-1 and displaced Bim from the Mcl-1/Bim complex, freeing Bim to trigger the mitochondrial apoptotic pathway. Together, our findings indicate that NOXA and Mcl-1 are critical determinants for gossypol-mediated cell death in ABT-737-resistant cells. These data therefore reveal novel insight into mechanisms of acquired resistance to ABT-737.
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