Bcl-2 inhibitors as anti-cancer therapeutics: The impact of and on calcium signaling.
Cell Calcium
; 70: 102-116, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-28705421
ABSTRACT
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.
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Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-bcl-2
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Sinalização do Cálcio
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Antineoplásicos
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article