Modulation of Signaling Enhances the Efficacy of the Combination of Satraplatin and Erlotinib

Title:Modulation of Signaling Enhances the Efficacy of the Combination of Satraplatin and Erlotinib

Volume: 15 Issue: 14

Author(s): Abolfazl Avan, Auke D. Adema, Eveline K. Hoebe, Charlotte M. Huijts, Amir Avan, Gareth J. Veal, Rob Ruijtenbeek, Katja Wosikowski and Godefridus J. Peters

Affiliation:

Keywords: Akt, colon cancer, Erk, erlotinib, lung cancer, satraplatin, signaling.

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.

Cite this article as:

Avan Abolfazl, Adema D. Auke, Hoebe K. Eveline, Huijts M. Charlotte, Avan Amir, Veal J. Gareth, Ruijtenbeek Rob, Wosikowski Katja and Peters J. Godefridus, Modulation of Signaling Enhances the Efficacy of the Combination of Satraplatin and Erlotinib, Current Drug Targets 2014; 15 (14) . https://dx.doi.org/10.2174/1389450115666141107110321