Combined effect of protein kinase B inhibitor or extracellular signal-regulated kinase inhibitor against farnesyltransferase inhibition-induced apoptosis in SiHa cells

Abstract

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 microM, 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.