期刊
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
卷 379, 期 3, 页码 291-303出版社
SPRINGER
DOI: 10.1007/s00210-008-0359-7
关键词
Farnesyltransferase inhibitor; Akt and ERK inhibitors; Mitochondrial membrane permeability change; Cervical SiHa cells; Differential modulation
The present study investigated the combined effect of Akt or extracellular signal-regulated kinase (ERK) inhibition in the presence of farnesyltransferase inhibitor against human cervix and uterus tumor cell line SiHa cells. Farnesyltransferase inhibitor may induce apoptosis through the mitochondria-mediated process and inhibition of the MEK, ERK, and Akt activity. Inhibitors of Akt and ERK at low concentrations seem to prevent the farnesyltransferase inhibitor-induced apoptosis in cervical SiHa cells by suppressing the mitochondrial membrane permeability change that leads to cytochrome c release and caspase-3 activation. These effects may be associated with inhibition of the reactive oxygen species formation and glutathione depletion. In contrast, at higher concentrations more than 1 mu M, the Akt inhibitor and ERK inhibitor seem to exhibit an additive toxic effect against farnesyltransferase inhibitor-induced apoptosis by increasing mitochondrial membrane permeability change and oxidative stress, which may not involve inhibition of MEK, ERK, and Akt activity.
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