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Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro. | LitMetric

Role of Mcl-1 in regulation of cell death in human induced pluripotent stem cell-derived cardiomyocytes in vitro.

Toxicol Appl Pharmacol

Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address:

Published: December 2018

AI Article Synopsis

  • - Targeting Mcl-1, an anti-apoptotic protein, shows promise for treating certain cancers but poses risks for heart health due to its role in cardiomyocytes, the heart's muscle cells.
  • - Research demonstrated that knocking down Mcl-1 in human stem cell-derived cardiomyocytes led to increased signs of cell stress, mitochondrial damage, and changes in heart cell function after 14 days.
  • - The study found that Mcl-1 and another protein, Bcl-xL, work together to protect heart cells; therefore, drugs targeting Mcl-1 might be safe to use if Bcl-xL remains functional.

Article Abstract

Targeting the anti-apoptotic protein Mcl-1 holds a promise to improve therapy of multiple types of Mcl-1 dependent cancers but raises concerns of on-target cardiotoxicity due to the presence and reported role of Mcl-1 in heart. Herein, we investigated the importance of Mcl-1 in the survival and contractile function of human pluripotent stem cell-derived cardiomyocytes in culture. Effective knockdown of Mcl-1 with siRNAs reproducibly resulted in early (measured at Day 3) marginal alterations in caspase 3/7 activity, LDH leakage, ATP content and cellular impedance. After 14 days of Mcl-1 knockdown, loss of mitochondrial membrane potential, deteriorating effects on mitochondrial ultrastructure, and alterations in beat rate and amplitude were revealed. Inhibition of Bcl-xL by siRNA-mediated knockdown or selective inhibitors did not cause any overt cellular responses except for a minimal increase in caspase 3/7 activity; however, loss of Mcl-1 concomitant with down-regulated Bcl-xL activated apoptosis and caused extensive cell death as reflected by an 80% loss in cell index, activation of caspase-3 with associated PARP cleavage, and a decrease in beat amplitude and mitochondrial membrane potential after 3 days of Mcl-1/Bcl-xL knockdown., Together, these findings suggest that Mcl-1 and Bcl-xL provide duplicate safeguard measures in maintaining structural and functional integrity of cardiomyocytes. Hence, BH3-mimetic drugs targeting Mcl-1 may be well tolerated in the presence of intact Bcl-xL.

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Source
http://dx.doi.org/10.1016/j.taap.2018.09.041DOI Listing

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