ArticleApoptosis : an international journal on programmed cell death2014
The putative BH3 mimetic S1 sensitizes leukemia to ABT-737 by increasing reactive oxygen species, inducing endoplasmic reticulum stress, and upregulating the BH3-only protein NOXA.
Article in Apoptosis : an international journal on programmed cell death, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- UPR/ATF4/Noxa pathway overactivation through SERCA2 inhibition or ONC201 treatment combined with ABT-737 triggers apoptosis in chemoresistant ovarian cancer cells and patient-derived tumor organoids.Cell death & disease · 2026Article
- Multifaceted Roles of Bcl-2 Family Proteins: Regulatory Roles in Apoptosis, Physiological Functions, and Therapeutic Potential.Current medical science · 2025Review
- ER Stress and Unfolded Protein Response in Leukemia: Friend, Foe, or Both?Biomolecules · 2021Review
- Chemical hypoxia induces apoptosis of human pluripotent stem cells by a NOXA-mediated HIF-1α and HIF-2α independent mechanism.Scientific reports · 2020Article
- AT101 [(-)-Gossypol] Selectively Inhibits MCL1 and Sensitizes Carcinoma to BH3 Mimetics by Inducing and Stabilizing NOXA.Cancers · 2020Article
- Clinical Review: Navitoclax as a Pro-Apoptotic and Anti-Fibrotic Agent.Frontiers in pharmacology · 2020Review
- ABT-263 exhibits apoptosis-inducing potential in oral cancer cells by targeting C/EBP-homologous protein.Cellular oncology (Dordrecht, Netherlands) · 2019Article
- Confounding off-target effects of BH3 mimetics at commonly used concentrations: MIM1, UMI-77, and A-1210477.Cell death & disease · 2019Article
- Systematic mapping of BCL-2 gene dependencies in cancer reveals molecular determinants of BH3 mimetic sensitivity.Nature communications · 2018Article
- Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays.Oncotarget · 2017Review
- BCL2 Inhibitors as Anticancer Drugs: A Plethora of Misleading BH3 Mimetics.Molecular cancer therapeutics · 2016Review
- Attacking cancer's Achilles heel: antagonism of anti-apoptotic BCL-2 family members.The FEBS journal · 2016Review
- Inhibition of MARCH5 ubiquitin ligase abrogates MCL1-dependent resistance to BH3 mimetics via NOXA.Oncotarget · 2016Article
- Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105.Cancer biology & therapy · 2016Article
- New dimension in therapeutic targeting of BCL-2 family proteins.Oncotarget · 2015Review
- Small molecule Mcl-1 inhibitors for the treatment of cancer.Pharmacology & therapeutics · 2015Review
- [Effect and significance of BH3-only protein in targeted therapy of non-small cell lung cancer].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2014Review
- The ratio of Mcl-1 and Noxa determines ABT737 resistance in squamous cell carcinoma of the skin.Cell death & disease · 2014Article
- Gossypol increases expression of the pro-apoptotic BH3-only protein NOXA through a novel mechanism involving phospholipase A2, cytoplasmic calcium, and endoplasmic reticulum stress.The Journal of biological chemistry · 2014Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
S1 is a putative BH3 mimetic proposed to inhibit BCL2 and MCL1 based on cell-free assays. However, we previously demonstrated that it failed to inhibit BCL2 or induce apoptosis in chronic lymphocytic leukemia (CLL) cells, which are dependent on BCL2 for survival. In contrast, we show here that S1 rapidly increases reactive oxygen species, initiates endoplasmic reticulum stress, and upregulates the BH3-only protein NOXA. The BCL2 inhibitors, ABT-737, ABT-263, and ABT-199, have demonstrated pro-apoptotic efficacy in cell lines, while ABT-263 and ABT-199 have demonstrated efficacy in early clinical trials. Resistance to these inhibitors arises from the upregulation of anti-apoptotic factors, such as MCL1, BFL1, and BCLXL. This resistance can be induced by co-culturing CLL cells on a stromal cell line that mimics the microenvironment found in patients. Since NOXA can inhibit MCL1, BFL1, and BCLXL, we hypothesized that S1 may overcome resistance to ABT-737. Here we demonstrate that S1 induces NOXA-dependent sensitization to ABT-737 in a human promyelocytic leukemia cell line (NB4). Furthermore, S1 sensitized CLL cells to ABT-737 ex vivo, and overcame resistance to ABT-737 induced by co-culturing CLL cells with stroma.
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