Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and

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Published on: January 7, 2019

Girija Dasmahapatra1, Nitin Yerram, Yun Dai

  • 1Department of Medicine, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298, USA.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|July 20, 2007
PubMed
Abstract

Insights

Combining vorinostat and sorafenib synergistically kills chronic myelogenous leukemia (CML) cells by down-regulating Mcl-1 and inhibiting p21(CIP1) induction, offering a potential new therapy for CML.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm.
  • Imatinib mesylate is a tyrosine kinase inhibitor used to treat CML.
  • Resistance to imatinib can develop, necessitating alternative treatment strategies.

Purpose of the Study:

  • To investigate the synergistic effects of sorafenib and vorinostat in CML cells.
  • To examine the impact of this combination on imatinib-sensitive and resistant CML cells.
  • To elucidate the underlying molecular mechanisms of cell death induction.

Main Methods:

  • Utilized K562, LAMA 84, and primary CML patient-derived CD34(+) cells.
  • Administered vorinostat followed by sorafenib.
  • Assessed cell viability, apoptosis, signaling pathways, and gene expression using flow cytometry, clonogenic assays, Western blotting, and RT-PCR.

Main Results:

  • Combined vorinostat and sorafenib treatment induced significant cell death and mitochondrial injury in Bcr/Abl(+) CML cells, including imatinib-resistant and primary patient cells.
  • The regimen inhibited colony formation and triggered apoptosis via mitochondrial dysfunction, caspase activation, and poly(ADP-ribose) polymerase cleavage.
  • Down-regulation of Mcl-1 and inhibition of p21(CIP1) induction were key mechanisms, with Mcl-1 down-regulation being caspase and transcription independent.

Conclusions:

  • Vorinostat and sorafenib exhibit synergistic apoptosis-inducing effects in CML cells.
  • The combination therapy targets Mcl-1 down-regulation and p21(CIP1) induction inhibition.
  • This combination represents a promising therapeutic approach for CML treatment, particularly in cases of imatinib resistance.

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