Bcl-2 inhibitors as anti-cancer therapeutics: The impact of and on calcium signaling |
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Affiliation: | 1. Dipartimento di Farmacia e Biotecnologie (FABIT), Università di Bologna, Bologna, Italy;2. IRCCS Istituto delle Scienze Neurologiche di Bologna (ISNB), Ospedale Bellaria, Bologna, Italy;3. Unità di Neurologia, Dipartimento di Scienze Biomediche e Neuromotorie (DIBINEM), Università di Bologna, Bologna, Italy;4. Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA |
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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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Keywords: | Apoptosis Anti-apoptotic proteins Small molecule inhibitors BH3 mimetics BH4-domain-targeting compounds |
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