ArticleMolecular pharmacology2009
Dual mechanisms of sHA 14-1 in inducing cell death through endoplasmic reticulum and mitochondria.
Article in Molecular pharmacology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 53 citations in OpenAlex.
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- Notch Inhibitors and BH3 Mimetics in T-Cell Acute Lymphoblastic Leukemia.International journal of molecular sciences · 2024Review
- Reappraisal of the fundamental mechanisms of the sHA14-1 molecule as a Bcl-2/Bcl-XL ligand in the context of anticancer therapy: A cell biological study.Journal of biological methods · 2024Article
- Acute ATP loss during irreversible electroporation mediates caspase independent cell death.Bioelectrochemistry (Amsterdam, Netherlands) · 2023Article
- Deregulated calcium signaling in blood cancer: Underlying mechanisms and therapeutic potential.Frontiers in oncology · 2022Review
- Targeting oncogenic Notch signaling with SERCA inhibitors.Journal of hematology & oncology · 2021Review
- TMPRSS13 promotes cell survival, invasion, and resistance to drug-induced apoptosis in colorectal cancer.Scientific reports · 2020Article
- CXL146, a Novel 4Molecular pharmacology · 2020Article
- ABT-199 (Venetoclax), a BH3-mimetic Bcl-2 inhibitor, does not cause CaBritish journal of pharmacology · 2019Article
- Exploring the Structure-Activity Relationship and Mechanism of a Chromene Scaffold (CXL Series) for Its Selective Antiproliferative Activity toward Multidrug-Resistant Cancer Cells.Journal of medicinal chemistry · 2018Article
- Emerging molecular mechanisms in chemotherapy: CaCell death & disease · 2018Review
- BH3 mimetic-elicited CaCell death & disease · 2017Article
- A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2.Oncotarget · 2015Article
- The role of BH3-mimetic drugs in the treatment of pediatric hepatoblastoma.International journal of molecular sciences · 2015Review
- Discovery of enzyme modulators via high-throughput time-resolved FRET in living cells.Journal of biomolecular screening · 2014Article
- A novel SERCA inhibitor demonstrates synergy with classic SERCA inhibitors and targets multidrug-resistant AML.Molecular pharmaceutics · 2013Article
- HA14-1, but not the BH3 mimetic ABT-737, causes Ca2+ dysregulation in platelets and human cell lines.Haematologica · 2013Article
- Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017): a novel scaffold that resensitizes multidrug resistant leukemia cells to chemotherapy.ACS chemical biology · 2013Article
- Structure-activity relationship (SAR) study of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and the potential of the lead against multidrug resistance in cancer treatment.Journal of medicinal chemistry · 2012Article
- The BH3 mimetic HA14-1 enhances 5-fluorouracil-induced autophagy and type II cell death in oesophageal cancer cells.British journal of cancer · 2012Article
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
HA 14-1 is a small-molecule Bcl-2 antagonist that promotes apoptosis in malignant cells, but its mechanism of action is not well defined. We recently reported that HA 14-1 has a half-life of only 15 min in vitro, which led us to develop a stable analog of HA 14-1 (sHA 14-1). The current study characterizes its mode of action. Because of the antiapoptotic function of Bcl-2 family proteins on the endoplasmic reticulum (ER) and mitochondria, the effect of sHA 14-1 on both organelles was evaluated. sHA 14-1 induced ER calcium release in human leukemic cells within 1 min, followed by induction of the ER stress-inducible transcription factor ATF4. Similar kinetics and stronger intensity of ER calcium release were induced by the sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA) inhibitor thapsigargin, accompanied by similar kinetics and intensity of ATF4 induction. sHA 14-1 directly inhibited SERCA enzymatic activity but had no effect on the inositol triphosphate receptor. Evaluation of the mitochondrial pathway showed that sHA 14-1 triggered a loss of mitochondrial transmembrane potential (Delta psi m) and weak caspase-9 activation, whereas thapsigargin had no effect. (R)-4-(3-Dimethylamino-1-phenylsulfanylmethyl-propylamino)-N-{4-[4-(4'-chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-benzoyl}-3-nitrobenzenesulfonamide (ABT-737), a well established small-molecule Bcl-2 antagonist, rapidly induced loss of Delta psi m and caspase-9 activation but had no effect on the ER. The pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone had some protective effect on sHA 14-1-induced cell death. These collective results suggest a unique dual targeting mechanism of sHA 14-1 on the apoptotic resistance machinery of tumor cells that includes antiapoptotic Bcl-2 family proteins and SERCA proteins.
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