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Modulation of signaling enhances the efficacy of the combination of satraplatin and erlotinib.
- Source :
-
Current drug targets [Curr Drug Targets] 2014; Vol. 15 (14), pp. 1312-21. - Publication Year :
- 2014
-
Abstract
- Unlabelled: 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).<br />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.
- Subjects :
- Apoptosis
Cell Cycle drug effects
Cell Line, Tumor
Drug Synergism
Drug Therapy, Combination
Erlotinib Hydrochloride
Gene Expression Regulation, Neoplastic drug effects
Humans
Neoplasms drug therapy
Neoplasms pathology
Phosphorylation drug effects
Antineoplastic Agents pharmacology
DNA Adducts metabolism
Neoplasms metabolism
Organoplatinum Compounds pharmacology
Quinazolines pharmacology
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1873-5592
- Volume :
- 15
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Current drug targets
- Publication Type :
- Academic Journal
- Accession number :
- 25382189
- Full Text :
- https://doi.org/10.2174/1389450115666141107110321