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

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

Journal Name: Current Drug Targets

Volume 15 , Issue 14 , 2014

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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.

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

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Article Details

VOLUME: 15
ISSUE: 14
Year: 2014
Page: [1312 - 1321]
Pages: 10
DOI: 10.2174/1389450115666141107110321
Price: $58

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