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Mutations of p53 decrease sensitivity to the anthracycline treatments in bladder cancer cells

Sony Pandey1, Jennifer Bourn1,2, Maria Cekanova1,2

  • 1Department of Small Animal Clinical Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, Tennessee 37996, USA.

Oncotarget
|July 10, 2018
PubMed

Insights

Novel anthracyclines AD 312 and AD 198 show efficacy against bladder cancer by inducing apoptosis, particularly in wild-type p53 cells. Drug resistance in mutated p53 bladder cancer cells correlates with TP53 mutations, suggesting combination therapies.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Doxorubicin (Dox) causes cardiotoxicity, necessitating the development of safer anthracyclines.
  • Novel non-cardiotoxic anthracyclines, AD 312 and AD 198, have been synthesized.

Purpose of the Study:

  • To assess the efficacy of novel anthracyclines (AD 312, AD 198) in human bladder cancer cells.
  • To investigate the mechanisms of anthracycline-induced apoptosis and cell viability inhibition.
  • To evaluate the role of wild-type (wt) and mutated (mt) p53 protein in drug response.

Main Methods:

  • Tested anthracycline efficacy in bladder cancer cell lines with wt p53 (RT4, SW780) and mt p53 (UM-UC-3, 5637, T-24, J82, TCCSUP).
  • Analyzed p53 protein expression, caspase 3/7 activation, and PARP cleavage.
  • Utilized p53 siRNA and co-treatment with PRIMA-1 to explore drug resistance mechanisms.
  • Investigated c-myc expression in response to anthracyclines.

Main Results:

  • Anthracyclines inhibited cell viability in TCC cells, with reduced efficacy in mt-p53 cells, especially drug-resistant J82 and TCCSUP.
  • Anthracyclines upregulated wt p53 but not mt p53.
  • Apoptosis markers (caspase 3/7, PARP cleavage) were activated in wt-p53 cells and some mt-p53 cells, but not in J82 and TCCSUP.
  • p53 siRNA blocked anthracycline-induced PARP cleavage in wt-p53 cells.
  • AD 198 combined with PRIMA-1 inhibited mt-p53 J82 cell viability.
  • AD 198 reduced c-myc expression in mt-p53 cells but not in wt-p53 cells.

Conclusions:

  • Anthracycline resistance in bladder cancer correlates with TP53 mutations in the tetramerization domain.
  • AD 312 and AD 198 are promising for bladder cancer treatment, potentially enhanced by PRIMA-1.
Keywords:
AD 198AD 312PRIMA-1bladder cancerp53 siRNA

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