Cisplatin is widely used for the treatment of solid tumours including small cell
lung cancers, but its success is often compromised by relapse and resistance to further treatment.
Extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt are two major cell survival pathways that are upregulated and activated in
lung cancer tissues. Phosphorylated ERK1/2 (p-ERK1/2) and Akt (p-Akt) can be further stimulated by chemotherapeutics in
cancer cells. Although individually targeting the ERK1/2 or Akt pathway has been reported to sensitize
cancer cells to
therapy, the effect of concurrently blocking these two pathways on the sensitivity of
lung cancer cells to
cisplatin has not been investigated. In the present study, we aimed to determine whether the ERK1/2 and Akt pathways contribute to
cisplatin resistance in human
small cell lung cancer A549 cells. The results showed that
cisplatin activates p-ERK1/2 and p-Akt in A549 cells. Blockade of either of these pathways with chemical inhibitors moderately sensitized A549 cells to
cisplatin-induced apoptosis and reduced cell viability. Strikingly, concurrent inhibition of p-ERK1/2 and p-Akt significantly potentiated
cisplatin cytotoxicity in vitro and in vivo. The sensitization of A549 cells to
cisplatin cytotoxicity induced by p-Akt inhibition was mediated by the upregulation of PUMA, whereas that induced by p-ERK1/2 inhibition occurred by Bcl-2 downregulation. These data indicate that the cooperative effects of p-ERK1/2 and p-Akt on attenuating
cisplatin cytotoxicity are mediated by PUMA and Bcl-2 regulation, and concurrently blocking these pathways may be an effective strategy for improving the efficacy of
cisplatin as anticancer treatment.