BCL-XL ACTIVITY INFLUENCES OUTCOME OF THE MITOTIC ARREST
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Date
2022-09-15
Authors
Suleimenov, M.
Bekbayev, S.
Ten, M.
Suleimenova, N.
Tlegenova, M.
Nurmagambetova, A.
Kauanova, S.
Vorobjev, I.
Journal Title
Journal ISSN
Volume Title
Publisher
Frontiers in Pharmacology
Abstract
Microtubule-targeting (MT) drugs taxanes and vinca alkaloids are widely used as
chemotherapeutic agents against different tumors for more than 30 years
because of their ability to block mitotic progression by disrupting the mitotic
spindle and activating the spindle assembly checkpoint (SAC) for a prolonged
period of time. However, responses to mitotic arrest are different—some cells
die during mitotic arrest, whereas others undergo mitotic slippage and survive
becoming able for proliferation. Using normal fibroblasts and several cancer cell
types we determined two critical doses, T1 and T2, of mitotic inhibitors
(nocodazole, Taxol, and vinorelbine). T1 is the maximal dose cells can
tolerate undergoing normal division, and T2 is the minimal mitostatic dose,
wherein > 90% of mitotic cells are arrested in mitosis. In all studied cell lines after
treatment with mitotic inhibitors in a dose above T2 cells had entered mitosis
either die or undergo mitotic slippage. We show that for all three drugs used cell
death during mitotic arrest and after slippage proceeded via mitochondriadependent
apoptosis. We determined two types of cancer cells: sensitive to
mitotic arrest, that is, undergoing death in mitosis (DiM) frequently, and resistant
to mitotic arrest, that is, undergoing mitotic slippage followed by prolonged
survival. We then determined that inhibition of Bcl-xL, but not other antiapoptotic
proteins of the Bcl-2 group that regulate MOMP, make resistant
cells susceptible to DiM induced by mitotic inhibitors. Combined treatment with
MT drugs and highly specific Bcl-xL inhibitors A-1155643 or A-1331852 allows
achieving 100% DiM in a time significantly shorter than maximal duration of
mitotic arrest in all types of cultured cells tested. We further examined efficacy
of sequential treatment of cultured cells using mitotic inhibitors followed by
inhibitors of Bcl-xL anti-apoptotic protein and for the first time show that
sensitivity to Bcl-xL inhibitors rapidly declines after mitotic slippage. Thus
sequential use of mitotic inhibitors and inhibitors of Bcl-xL anti-apoptotic
protein will be efficient only if the Bcl-xL inhibitor will be added before
mitotic slippage occurs or soon afterward. The combined treatment
proposed might be an efficient approach to anti-cancer therapy.
Description
Keywords
Type of access: Open Access, mitotic arrest, anti-mitotic drugs, apoptosis, Bcl-2 proteins, flow cytometry, live cell imaging
Citation
Suleimenov, M., Bekbayev, S., Ten, M., Suleimenova, N., Tlegenova, M., Nurmagambetova, A., Kauanova, S., & Vorobjev, I. (2022). Bcl-xL activity influences outcome of the mitotic arrest. Frontiers in Pharmacology, 13. https://doi.org/10.3389/fphar.2022.933112