Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis
Open Access
- 25 June 2020
- Vol. 12 (6), 1694
- https://doi.org/10.3390/cancers12061694
Abstract
Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development.Funding Information
- Estonian Research Competency Council (MOBTT39)
This publication has 46 references indexed in Scilit:
- Anticancer compound ABT-263 accelerates apoptosis in virus-infected cells and imbalances cytokine production and lowers survival rates of infected miceCell Death & Disease, 2013
- Mechanisms of Action of Bcl-2 Family ProteinsCold Spring Harbor Perspectives in Biology, 2013
- 81 A new series of biologically active DNA minor groove binders based on bisbenzimidazole and benzimidazole-pyrrole motivesJournal of Biomolecular Structure and Dynamics, 2013
- Obatoclax, Saliphenylhalamide, and Gemcitabine Inhibit Influenza A Virus InfectionOnline Journal of Public Health Informatics, 2012
- The Bcl-2/Bcl-XL/Bcl-w Inhibitor, Navitoclax, Enhances the Activity of Chemotherapeutic Agents In Vitro and In VivoMolecular Cancer Therapeutics, 2011
- Apoptosis in cancer: from pathogenesis to treatmentJournal of Experimental & Clinical Cancer Research, 2011
- Apoptosis: A Review of Programmed Cell DeathToxicologic Pathology, 2007
- Different levels of p53 induced either apoptosis or cell cycle arrest in a doxycycline-regulated hepatocellular carcinoma cell line in vitroApoptosis, 2006
- Application of Real-Time Cell Electronic Sensing (RT-CES) Technology to Cell-Based AssaysASSAY and Drug Development Technologies, 2004
- Gp130 and ras mediated signaling in human plasma cell line INA-6: a cytokine-regulated tumor model for plasmacytomaThe Hematology Journal, 2001