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Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas

Santi Rello-Varona1, Miriam Fuentes-Guirado2, Roser López-Alemany2

  • 1Sarcoma Research Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. santirellovarona@gmail.com.

Scientific Reports
|March 9, 2019
PubMed

Insights

Dinaciclib, a CDK inhibitor, shows potential against soft-tissue sarcomas (STS) by inducing apoptosis. Targeting Bcl-xL offers a promising therapeutic strategy for advanced STS, overcoming resistance mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Soft-tissue sarcomas (STS) are rare, aggressive cancers with poor outcomes, especially in metastatic stages.
  • Current treatments for metastatic STS are limited, necessitating novel therapeutic approaches.
  • Cyclin-dependent kinase (CDK) inhibitors represent a potential class of drugs for cancer therapy.

Purpose of the Study:

  • To evaluate the efficacy of Dinaciclib, a CDK inhibitor, against various soft-tissue sarcoma models in vitro.
  • To elucidate the mechanism of action of Dinaciclib, focusing on cell death pathways and key regulatory proteins.
  • To explore combination therapies involving Dinaciclib or Bcl-xL inhibition for enhanced STS treatment.

Main Methods:

  • In vitro inactivation of diverse STS models using Dinaciclib at nanomolar concentrations.
  • Analysis of cell death induction mechanisms, identifying the mitochondrial apoptosis pathway.
  • Assessment of anti-apoptotic protein Bcl-xL, pro-apoptotic proteins BIM and PUMA, and protein synthesis disruption.
  • Combination studies with BH3-mimetics and conventional chemotherapy (Gemcitabine) with Bcl-xL inhibitor A-1331852.

Main Results:

  • Dinaciclib effectively inhibited STS cell growth in vitro.
  • Apoptosis was mediated through the mitochondrial pathway, with Bcl-xL identified as a key regulator.
  • Low levels of BIM and PUMA in resistant cell lines were insufficient to overcome Bcl-xL's anti-apoptotic function.
  • Combination of Dinaciclib with BH3-mimetics induced rapid apoptosis in vitro, but liver toxicity limited in vivo studies.
  • Bcl-xL inhibitor A-1331852 synergized with Gemcitabine.

Conclusions:

  • Dinaciclib demonstrates in vitro efficacy against STS by targeting cell cycle and protein synthesis.
  • Bcl-xL plays a critical role in STS resistance to Dinaciclib-induced apoptosis.
  • Targeting Bcl-xL, potentially in combination with chemotherapy, represents a promising therapeutic strategy for STS treatment.

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