Modulation of signaling enhances the efficacy of the combination of satraplatin and erlotinib

Curr Drug Targets. 2014;15(14):1312-21. doi: 10.2174/1389450115666141107110321.

Abstract

The active metabolite (JM118) of the oral platinum analog satraplatin (JM216) was investigated for potential synergism with erlotinib, an epidermal growth factor receptor (EGFR) inhibitor. JM118 sensitivity of 7 cancer cell lines (ovarian: 2008, A2780; colon: Lovo92, WiDr; lung: A549, SW1573; epidermoid: A431), was enhanced most pronounced when JM118 preceded erlotinib, which was associated with increased formation of DNA-platinum adducts. The combination increased G2/M phase accumulation and enhanced apoptosis. JM118 increased the phosphorylation of the cell cycle proteins CDK2 and CHK1 after 24 hr exposure. JM118/erlotinib enhanced Erk and Akt phosphorylation after 2 hr. JM118 significantly decreased the phosphorylation of PTEN, VEGFR, EPHA1, ERBB4, FGF-R, andSTAT3 by 20 (PTEN) to >90% (STAT3).

Conclusion: Erlotinib enhanced the effects of JM118, even in cells with mutations in Ras. The mechanism of synergy involved a combination of effects on platinum-DNA adduct formation, cell cycle distribution and signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • DNA Adducts / metabolism*
  • Drug Synergism
  • Drug Therapy, Combination
  • Erlotinib Hydrochloride
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Neoplasms / drug therapy
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Organoplatinum Compounds / pharmacology*
  • Phosphorylation / drug effects
  • Quinazolines / pharmacology*
  • Signal Transduction / drug effects*

Substances

  • Antineoplastic Agents
  • DNA Adducts
  • Organoplatinum Compounds
  • Quinazolines
  • amminedichloro(cyclohexylamine)platinum(II)
  • satraplatin
  • Erlotinib Hydrochloride