BCL-xL-selective BH3 mimetic sensitizes rhabdomyosarcoma cells to chemotherapeutics by activation of the mitochondrial pathway of apoptosis

Sara Fatima Faqar-Uz-Zaman, Ulrike Heinicke, Michael Torsten Meister, Meike Vogler, Simone Fulda

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)

Abstract

BH3 mimetics are a promising new class of anticancer agents that inhibit antiapoptotic BCL-2 proteins. Here, we report that BH3 mimetics selectively targeting BCL-xL, BCL-2 or MCL-1 (i.e. A-1331852, ABT-199, A-1210477) act in concert with multiple chemotherapeutic agents (i.e. vincristine (VCR), etoposide (ETO), doxorubicin, actinomycin D and cyclophosphamide) to induce apoptosis in rhabdomyosarcoma (RMS) cells. Similarly, genetic knockdown of BCL-xL primes RMS cells to VCR- or ETO-induced cell death, highlighting the importance of BCL-xL in mediating chemotherapy resistance in RMS. A-1331852 and VCR or ETO cooperate to stimulate caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor zVAD.fmk rescues cells from cell death. Molecular studies reveal that VCR/A-1331852 co-treatment causes profound mitotic arrest, which initiates phosphorylation of BCL-2, thereby promoting its inactivation. Also, A-1331852 and VCR or ETO act together to trigger BAX and BAK activation, followed by loss of mitochondrial membrane potential (MMP). Consistently, overexpression of BCL-2 or MCL-1 markedly reduces VCR/A-1331852- or ETO/A-1331852-mediated apoptosis, underscoring that mitochondrial apoptosis represents a key event in synergistic drug interaction. In conclusion, our findings provide a rationale for the combination of BH3 mimetics with conventional chemotherapeutic agents to increase the chemosensitivity of RMS.

Original languageEnglish
Pages (from-to)131-142
Number of pages12
JournalCancer Letters
Volume412
DOIs
Publication statusPublished - 1 Jan 2018
Externally publishedYes

Keywords

  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Benzothiazoles/pharmacology
  • Cell Line, Tumor
  • Etoposide/pharmacology
  • Humans
  • Isoquinolines/pharmacology
  • Mitochondria/drug effects
  • Rhabdomyosarcoma/drug therapy
  • Vincristine/pharmacology
  • bcl-2-Associated X Protein/physiology
  • bcl-X Protein/antagonists & inhibitors

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