ArticleTranslational oncology2009
Endogenous Noxa Determines the Strong Proapoptotic Synergism of the BH3-Mimetic ABT-737 with Chemotherapeutic Agents in Human Melanoma Cells.
Article in Translational oncology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- Dacarbazine as a Positive Control in Melanoma Cell Lines (A375, SK-MEL-103, 1205Lu) and a Human Ex Vivo Skin Model.Advanced biology · 2026Article
- Integrated stress response activation induced by usnic acid alleviates BCL-2 inhibitor ABT-199 resistance in acute myeloid leukemia.Journal of advanced research · 2025Article
- BH3-Only Proteins Noxa and Puma Are Key Regulators of Induced Apoptosis.Life (Basel, Switzerland) · 2022Review
- LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells.Cancer cell international · 2021Article
- Bim, Puma and Noxa upregulation by Naftopidil sensitizes ovarian cancer to the BH3-mimetic ABT-737 and the MEK inhibitor Trametinib.Cell death & disease · 2020Article
- BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival.Cell death & disease · 2019Article
- Use of a MCL-1 inhibitor alone to de-bulk melanoma and in combination to kill melanoma initiating cells.Oncotarget · 2017Article
- c-FLIP and the NOXA/Mcl-1 axis participate in the synergistic effect of pemetrexed plus cisplatin in human choroidal melanoma cells.PloS one · 2017Article
- Article
- Imiquimod-induced apoptosis of melanoma cells is mediated by ER stress-dependent Noxa induction and enhanced by NF-κB inhibition.Journal of cellular and molecular medicine · 2016Article
- Antihelminthic benzimidazoles potentiate navitoclax (ABT-263) activity by inducing Noxa-dependent apoptosis in non-small cell lung cancer (NSCLC) cell lines.Cancer cell international · 2015Article
- EHMT2 inhibitor BIX-01294 induces apoptosis through PMAIP1-USP9X-MCL1 axis in human bladder cancer cells.Cancer cell international · 2015Article
- Parthenolide induces apoptosis via TNFRSF10B and PMAIP1 pathways in human lung cancer cells.Journal of experimental & clinical cancer research : CR · 2014Article
- MYC and EGR1 synergize to trigger tumor cell death by controlling NOXA and BIM transcription upon treatment with the proteasome inhibitor bortezomib.Nucleic acids research · 2014Article
- Targeting Bcl-2/Bcl-XL induces antitumor activity in uveal melanoma patient-derived xenografts.PloS one · 2014Article
- Article
- Systems analysis of apoptosis protein expression allows the case-specific prediction of cell death responsiveness of melanoma cells.Cell death and differentiation · 2013Article
- Proteasomal degradation of Mcl-1 by maritoclax induces apoptosis and enhances the efficacy of ABT-737 in melanoma cells.PloS one · 2013Article
- The downregulation of Mcl-1 via USP9X inhibition sensitizes solid tumors to Bcl-xl inhibition.BMC cancer · 2012Article
- Anti-cancer drug discovery and development: Bcl-2 family small molecule inhibitors.Communicative & integrative biology · 2012Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Human melanoma cells are very resistant to treatment with chemotherapeutic agents, and melanoma shows poor response to chemotherapeutic therapy. We describe a strong synergistic proapoptotic effect of the Bcl-2 family inhibitor ABT-737 and the standard antimelanoma drugs, namely, dacarbazine and fotemustine, and the experimental agent, imiquimod. Experiments with human melanoma cells, keratinocytes, and embryonic fibroblasts showed that all three agents activated the mitochondrial apoptosis pathway. ABT-737 on its own was ineffective in melanoma cells unless Mcl-1 was experimentally downregulated. However, ABT-737 strongly enhanced the proapoptotic activity of the chemotherapeutic drugs. Whereas cell death induction by all three agents involved the activity of both BH3-only proteins, Bim and Noxa, the combination with ABT-737 overcame the requirement for Bim. However, the synergism between ABT-737 and imiquimod or dacarbazine required endogenous Noxa, as demonstrated by experiments with Noxa-specific RNAi. Surprisingly, although Bim was activated, it was unable to replace Noxa. Studies of mitochondrial cytochrome c release using BH3 peptides confirmed that a main effect of dacarbazine, fotemustine, and imiquimod was to neutralize Mcl-1, thereby sensitizing mitochondria to the inhibition of other Bcl-2 family members through ABT-737. ABT-737 is thus a promising agent for combination therapy for human melanoma. Importantly, the efficacy of this therapy depends on endogenous Noxa, and the ability of chemotherapeutic drugs to activate Noxa may be a valuable predictor of their synergism with Bcl-2-targeting drugs.
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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.