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

  1. Author:
    Guo, Liang
    Eldridge, Sandy
    Furniss, Michael
    Mussio, Jodie
    Davis, Myrtle

  2. Author Address

    Laboratory of Investigative Toxicology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, United States. Electronic address: liang.guo@nih.gov., Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: sandy.eldridge@nih.gov., Laboratory of Investigative Toxicology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, United States. Electronic address: furnissm@mail.nih.gov., Laboratory of Investigative Toxicology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702, United States. Electronic address: mussiojk@mail.nih.gov., Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States. Electronic address: Myrtle.Davis@bms.com.,
    1. Year: 2018
    2. Date: Dec 1
    3. Epub Date: 2018 09 27
  2. Journal: Toxicology and applied pharmacology
    1. 360
    2. Pages: 88-98
  4. Type of Article: Article
  5. ISSN: 0041-008X
  1. 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. Copyright © 2018. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.taap.2018.09.041
  3. PMID: 30268579
  4. View record in Web of Science®
  5. WOS: 000451238100010
  6. PII : S0041-008X(18)30447-2

Library Notes

  1. Fiscal Year: FY2017-2018
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