AS602801, an Anticancer Stem Cell Candidate Drug, Reduces Survivin Expression and Sensitizes A2780 Ovarian Cancer Stem Cells to Carboplatin and Paclitaxel

Anticancer Res. 2018 Dec;38(12):6699-6706. doi: 10.21873/anticanres.13038.

Abstract

Background: AS602801, a novel inhibitor of c-Jun N-terminal kinase (JNK), suppresses tumor initiation capacity and metastatic potential of cancer stem cells (CSCs). However, it remains unknown whether this inhibitor can chemosensitize CSCs.

Materials and methods: Using A2780 CSLC, a CSC line derived from ovarian cancer, this study examined the combinational effects of AS602801 and carboplatin or paclitaxel and explored the mechanism of those effects.

Results: AS602801 chemosensitized A2780 CSLC cells to carboplatin and paclitaxel. With respect to the mechanism of chemosensitization, the expression of survivin, an anti-apoptotic protein, was reduced by AS602801. Pharmacological and genetic inhibition of survivin chemosensitized the cells to carboplatin and paclitaxel. Suppression of survivin by AS602801 was also observed in other types of CSCs and non-CSCs.

Conclusion: AS602801, which reduces survivin expression, can chemosensitize ovarian CSCs and is a candidate drug that targets the chemoresistance, tumor-initiating capacity and metastasis of CSCs.

Keywords: Drug repositioning; drug resistance; repurposing.

MeSH terms

  • A549 Cells
  • Benzothiazoles / pharmacology*
  • Carboplatin / pharmacology*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Drug Synergism
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Ovarian Neoplasms / pathology*
  • Paclitaxel / pharmacology*
  • Pyrimidines / pharmacology*
  • Survivin / genetics*
  • Survivin / metabolism

Substances

  • Benzothiazoles
  • Pyrimidines
  • Survivin
  • Carboplatin
  • Paclitaxel
  • bentamapimod