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:
关键词:
Akt，结肠癌，Erk，埃罗替尼，肺癌，赛特铂，信号
摘要: 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.
