DC120, a novel AKT inhibitor, preferentially suppresses nasopharyngeal carcinoma cancer stem-like cells by downregulating Sox2

Oncotarget. 2015 Mar 30;6(9):6944-58. doi: 10.18632/oncotarget.3128.

Abstract

Side population (SP) contains cancer stem-like cells (CSLCs). In this study, we characterized SP cells from nasopharyngeal carcinoma (NPC) cell lines and found that SP cells had a higher self-renewal ability in vitro and greater tumorigenicity in vivo. The AKT pathway was activated in NPC SP cells. DC120, a 2-pyrimidyl-5-amidothiazole inhibitor of the ATP binding site of AKT, inhibited phosphorylation of FKHRL1 and GSK-3β. DC120 inhibited SP fraction, the sphere-forming ability in vitro and growth of primary xenografts as well as secondary xenografts' tumor recurrence. This inhibition was accompanied by reduced expression of stem-related gene Sox2 due to induction of p27 and miR-30a. A combination of DC120 and CDDP more effectively inhibited NPC cells compared with monotherapy in vitro and in vivo. Clinical evaluation of DC120 is warranted.

Keywords: DC120; PKB/AKT; cancer stem-like cells; nasopharyngeal carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Antineoplastic Agents / chemistry
  • Binding Sites
  • Carcinoma
  • Cell Separation
  • Down-Regulation
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Mice, SCID
  • Nasopharyngeal Carcinoma
  • Nasopharyngeal Neoplasms / enzymology*
  • Neoplasm Recurrence, Local
  • Neoplastic Stem Cells / drug effects*
  • Phenotype
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidines / chemistry*
  • SOXB1 Transcription Factors / metabolism*
  • Thiazoles / chemistry*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • N-(1-amino-3-(2,4-dichlorophenyl)propan-2-yl)-2-(2-(methylamino)pyrimidin-4-yl)thiazole-5-carboxamide
  • Pyrimidines
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • Thiazoles
  • Adenosine Triphosphate
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3