期刊
CELL CALCIUM
卷 70, 期 -, 页码 102-116出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2017.05.014
关键词
Ca2+ signaling; Apoptosis; Anti-apoptotic proteins; Small molecule inhibitors; BH3 mimetics; BH4-domain-targeting compounds
类别
资金
- Research Foundation-Flanders (FWO)
- Emmanuel van der Schueren Fund of the Kom op tegen Kanker Action
- FWO [6.057.12, G.0819.13, G.0C91.14, G.0A34.16, W0.019.17N]
- Research Council of the KU Leuven [OT/14/101]
- Interuniversity Attraction Poles Program (Belgian Science Policy) [IAP/P7/13]
Bcl-2-protein family members are essential regulators of apoptosis. Anti-apoptotic Bcl-2 proteins ensure cell survival via different mechanisms, including via binding of pro-apoptotic Bcl-2-family members and the modulation of intracellular Ca2+-transport systems. Many cancer cells upregulate these proteins to overcome the consequences of ongoing oncogenic stress. Bcl-2 inhibition leading to cell death, therefore emerged as a novel cancer therapy. Different Bcl-2 inhibitors have already been developed including the hydrophobic cleft-targeting BH3 mimetics, which antagonize Bcl-2's ability to scaffold and neutralize pro-apoptotic Bcl-2-family members. As such, the BH3 mimetics have progressed into clinical studies as precision medicines. Furthermore, new inhibitors that target Bcl-2's BH4 domain have been developed as promising anti-cancer tools. Given Bcl-2's role in Ca2+ signaling, these drugs and tools can impact Ca2+ signaling. In addition to this, some Bcl-2 inhibitors may have off-target effects that cause Ca2+ signaling dysregulation not only in cancer cells but also in healthy cells, resulting in adverse effects. In this review, we aim to provide an up-to-date overview of the involvement of intracellular Ca2+ signaling in the working mechanism and off-target effects of the different Bcl-2-antagonizing small molecules and peptides. (C) 2017 Elsevier Ltd. All rights reserved.
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