ArticleRadiation oncology (London, England)2009
AT-101, a small molecule inhibitor of anti-apoptotic Bcl-2 family members, activates the SAPK/JNK pathway and enhances radiation-induced apoptosis.
Article in Radiation oncology (London, England), 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, 58 citations in OpenAlex.
- Targeting anti-apoptotic Bcl-2 by AT-101 to increase radiation efficacy: data from in vitro and clinical pharmacokinetic studies in head and neck cancer.Radiation oncology (London, England) · 2015Trial
- Mechanistic overview and suggested strategies to overcome BCL-2 inhibitor resistance inFrontiers in cell and developmental biology · 2026Review
- Follicle stimulating hormone controls granulosa cell glutamine synthesis to regulate ovulation.Protein & cell · 2024Article
- Unlocking the Therapeutic Potential of BCL-2 Associated Protein Family: Exploring BCL-2 Inhibitors in Cancer Therapy.Biomolecules & therapeutics · 2024Review
- Block Copolymer Encapsulation of Disarib, an Inhibitor of BCL2 for Improved Chemotherapeutic Potential.ACS omega · 2023Article
- Engineering the Tumor Immune Microenvironment through Minimally Invasive Interventions.Cancers · 2022Review
- Systematic Review of Gossypol/AT-101 in Cancer Clinical Trials.Pharmaceuticals (Basel, Switzerland) · 2022Review
- ABT-737, a BH3 Mimetic, Enhances the Therapeutic Effects of Ionizing Radiation in K-ras Mutant Non-Small Cell Lung Cancer Preclinical Model.Yonsei medical journal · 2022Article
- Enhancing radiation response by a second-generation TRAIL receptor agonist using a new in vitro organoid model system.Clinical and translational radiation oncology · 2020Article
- Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox.Cancers · 2019Review
- Drugs and Clinical Approaches Targeting the Antiapoptotic Protein: A Review.BioMed research international · 2019Review
- Effect of the BH3 Mimetic Polyphenol (-)-Gossypol (AT-101) on theFrontiers in pharmacology · 2018Article
- Injectable (-)-gossypol-loaded Pluronic P85 micelles for cancer chemoradiotherapy.International journal of radiation biology · 2017Article
- Thioridazine Sensitizes Esophageal Carcinoma Cell Lines to Radiotherapy-Induced Apoptosis In Vitro and In Vivo.Medical science monitor : international medical journal of experimental and clinical research · 2016Article
- AT101 exerts a synergetic efficacy in gastric cancer patients with 5-FU based treatment through promoting apoptosis and autophagy.Oncotarget · 2016Article
- The P2X7 receptor regulates cell survival, migration and invasion of pancreatic ductal adenocarcinoma cells.Molecular cancer · 2015Article
- Examination of Gossypol-Pluronic Micelles as Potential Radiosensitizers.The AAPS journal · 2015Article
- Gossypol Acetic Acid Prevents Oxidative Stress-Induced Retinal Pigment Epithelial Necrosis by Regulating the FoxO3/Sestrin2 Pathway.Molecular and cellular biology · 2015Article
- 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
- Current concepts in clinical radiation oncology.Radiation and environmental biophysics · 2014Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGossypol, a naturally occurring polyphenolic compound has been identified as a small molecule inhibitor of anti-apoptotic Bcl-2 family proteins. It induces apoptosis in a wide range of tumor cell lines and enhances chemotherapy- and radiation-induced cytotoxicity both in vitro and in vivo. Bcl-2 and related proteins are important inhibitors of apoptosis and frequently overexpressed in human tumors. Increased levels of these proteins confer radio- and chemoresistance and may be associated with poor prognosis. Consequently, inhibition of the anti-apoptotic functions of Bcl-2 family members represents a promising strategy to overcome resistance to anticancer therapies.
methodsWe tested the effect of (-)-gossypol, also denominated as AT-101, radiation and the combination of both on apoptosis induction in human leukemic cells, Jurkat T and U937. Because activation of the SAPK/JNK pathway is important for apoptosis induction by many different stress stimuli, and Bcl-X(L) is known to inhibit activation of SAPK/JNK, we also investigated the role of this signaling cascade in AT-101-induced apoptosis using a pharmacologic and genetic approach.
resultsAT-101 induced apoptosis in a time- and dose-dependent fashion, with ED50 values of 1.9 and 2.4 microM in Jurkat T and U937 cells, respectively. Isobolographic analysis revealed a synergistic interaction between AT-101 and radiation, which also appeared to be sequence-dependent. Like radiation, AT-101 activated SAPK/JNK which was blocked by the kinase inhibitor SP600125. In cells overexpressing a dominant-negative mutant of c-Jun, AT-101-induced apoptosis was significantly reduced.
conclusionOur data show that AT-101 strongly enhances radiation-induced apoptosis in human leukemic cells and indicate a requirement for the SAPK/JNK pathway in AT-101-induced apoptosis. This type of apoptosis modulation may overcome treatment resistance and lead to the development of new effective combination therapies.
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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.