6,7-di-O-acetylsinococuline (FK-3000) induces G2/M phase arrest in breast carcinomas through p38 MAPK phosphorylation and CDC25B dephosphorylation

Int J Oncol. 2015 Feb;46(2):578-86. doi: 10.3892/ijo.2014.2739. Epub 2014 Nov 7.

Abstract

We evaluated the cytostatic effect of 6,7-di-O-acetyl-sinococuline (FK-3000) isolated from Stephania delavayi Diels. against breast carcinoma cell lines MDA-MB‑231 and MCF-7. FK-3000 suppressed CDC25B phosphorylation directly and indirectly via p38 MAPK phosphorylation. CDC25B dephosphorylation decreased levels of cyclin B and phospho-CDC-2, and ultimately induced cell cycle arrest at the G2/M phase. The p38 MAPK inhibitor, SB 239063 blocked FK-3000-induced p38 MAPK phosphorylation and nuclear accumulation, but did not completely rescue cell death. Conclusively FK-3000 exerts its antiproliferative effect through two pathways: i) G2/M cell cycle arrest via downregulation of cyclin B and phospho-CDC2 by p38 MAPK phosphorylation and CDC25B dephosphorylation, and ii) p38 MAPK-independent induction of apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / administration & dosage*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Carcinoma / drug therapy*
  • Carcinoma / genetics
  • Carcinoma / pathology
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • MCF-7 Cells
  • Phosphorylation
  • cdc25 Phosphatases / biosynthesis*
  • p38 Mitogen-Activated Protein Kinases / biosynthesis*
  • p38 Mitogen-Activated Protein Kinases / genetics

Substances

  • Alkaloids
  • FK3000
  • p38 Mitogen-Activated Protein Kinases
  • CDC25B protein, human
  • cdc25 Phosphatases