Selective BH3 mimetics synergize with BET inhibition to induce mitochondrial apoptosis in rhabdomyosarcoma cells

Ufuk Erdogdu, Nadezda Dolgikh, Stephanie Laszig, Vinzenz Särchen, Michael T Meister, Marek Wanior, Stefan Knapp, Cathinka Boedicker

Research output: Contribution to journalArticlepeer-review

Abstract

BH3 mimetics are promising novel anticancer therapeutics. By selectively inhibiting BCL-2, BCL-xL, or MCL-1 (i.e. ABT-199, A-1331852, S63845) they shift the balance of pro- and anti-apoptotic proteins in favor of apoptosis. As Bromodomain and Extra Terminal (BET) protein inhibitors promote pro-apoptotic rebalancing, we evaluated the potential of the BET inhibitor JQ1 in combination with ABT-199, A-1331852 or S63845 in rhabdomyosarcoma (RMS) cells. The strongest synergistic interaction was identified for JQ1/A-1331852 and JQ1/S63845 co-treatment, which reduced cell viability and long-term clonogenic survival. Mechanistic studies revealed that JQ1 upregulated BIM and NOXA accompanied by downregulation of BCL-xL, promoting pro-apoptotic rebalancing of BCL-2 proteins. JQ1/A-1331852 and JQ1/S63845 co-treatment enhanced this pro-apoptotic rebalancing and triggered BAK- and BAX-dependent apoptosis since a) genetic silencing of BIM, BAK or BAX, b) inhibition of caspase activity with zVAD.fmk and c) overexpression of BCL-2 all rescued JQ1/A-1331852- and JQ1/S63845-induced cell death. Interestingly, NOXA played a different role in both treatments, as genetic silencing of NOXA significantly rescued from JQ1/A-1331852-mediated apoptosis but not from JQ1/S63845-mediated apoptosis. In summary, JQ1/A-1331852 and JQ1/S63845 co-treatment represent new promising therapeutic strategies to synergistically trigger mitochondrial apoptosis in RMS.

Original languageEnglish
Pages (from-to)109-119
Number of pages11
JournalNeoplasia (New York, N.Y.)
Volume24
Issue number2
DOIs
Publication statusPublished - Feb 2022
Externally publishedYes

Keywords

  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Biomimetics
  • Cell Line, Tumor
  • Drug Synergism
  • Humans
  • Mitochondria/drug effects
  • Nerve Tissue Proteins/antagonists & inhibitors
  • Peptide Fragments/pharmacology
  • Proto-Oncogene Proteins/pharmacology
  • Receptors, Cell Surface/antagonists & inhibitors
  • Rhabdomyosarcoma

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