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HDAC inhibition as a treatment concept to combat temsirolimus-resistant bladder cancer cells

Eva Juengel1,2, Ramin Najafi1, Jochen Rutz1

  • 1Department of Urology, Goethe-University, Frankfurt am Main, Germany.

Oncotarget
|January 5, 2018
PubMed
Abstract

Insights

Histone deacetylase (HDAC) inhibition with valproic acid (VPA) effectively combats temsirolimus-resistant bladder cancer. This combination therapy shows promise for treating advanced bladder cancer by overcoming acquired resistance to mTOR inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mechanistic target of rapamycin (mTOR) inhibitors show promise for advanced bladder cancer.
  • Acquired resistance to mTOR inhibitors like temsirolimus is a significant clinical challenge.
  • Histone deacetylase (HDAC) inhibition is explored as a strategy to overcome this resistance.

Purpose of the Study:

  • To investigate the impact of HDAC inhibition on temsirolimus-resistant bladder cancer cells.
  • To determine if HDAC blockade can circumvent resistance to mTOR inhibitors.
  • To evaluate the combination of temsirolimus and an HDAC inhibitor for bladder cancer treatment.

Main Methods:

  • Exposure of parental and temsirolimus-resistant bladder cancer cell lines (RT112res, UMUC-3res) to the HDAC inhibitor valproic acid (VPA).
  • Assessment of tumor cell growth, proliferation, cell cycle, and expression of cell cycle-regulating proteins.
  • Utilizing siRNA blockade to investigate the functional significance of specific proteins.

Main Results:

  • Valproic acid (VPA) significantly inhibited growth and proliferation, inducing G0/G1 phase arrest in resistant cells.
  • VPA treatment led to down-regulation of CDK1, cyclin B, CDK2, cyclin A, and Skp1 p19, with elevated p27.
  • Akt-mTOR signaling was deactivated, while histone H3 and H4 acetylation increased; CDK2 or cyclin A knockdown caused significant growth blockade.

Conclusions:

  • HDAC inhibition demonstrates a potent anti-cancer effect on temsirolimus-resistant bladder cancer cells.
  • The combination of temsirolimus and VPA presents an innovative therapeutic strategy for bladder cancer.
  • Targeting HDAC may overcome resistance mechanisms in advanced bladder cancer treated with mTOR inhibitors.
Keywords:
HDAC inhibitionbladder cancertemsirolimus-resistancetumor growthvalproic acid (VPA)

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