Although
carboplatin is one of the standard chemotherapeutic agents for
non-small cell lung cancer (NSCLC), it has limited therapeutic efficacy due to activation of a survival signaling pathway and the induction of multidrug resistance.
Curcumin, a natural compound isolated from the plant Curcuma longa, is known to sensitize
tumors to different chemotherapeutic agents. The aim of this study is to evaluate whether
curcumin can chemosensitize
lung cancer cells to
carboplatin and to analyze the signaling pathway underlying this synergism. We investigated the synergistic effect of both agents on cell proliferation, apoptosis, invasion, migration, and expression of related signaling
proteins using the human NSCLC cell line, A549. A549 cell was treated with different concentrations of
curcumin and
carboplatin alone and in combination. Combined treatment with
curcumin and
carboplatin inhibited
tumor cell growth, migration, and invasion compared with either
drug alone.
Matrix metalloproteinase (MMP)-2 and MMP-9 were more efficiently downregulated by co-treatment than by each treatment alone.
mRNA and
protein expression of
caspase-3 and
caspase-9 and proapoptotic genes was increased in cells treated with a combination of
curcumin and
carboplatin, whereas expression of the antiapoptotic Bcl-2 gene was suppressed. Co-treatment of both agents substantially suppressed NF-κB activation and increased expression of p53. Phosphorylation of Akt, a
protein upstream of NF-κB, was reduced, resulting in inhibition of the degradation of inhibitor of κB(IκBα), whereas the activity of
extracellular signal-regulated kinase (ERK1/2) was enhanced. Our study demonstrated that the synergistic antitumor activity of
curcumin combined with
carboplatin is mediated by multiple mechanisms involving suppression of NF-κB via inhibition of the Akt/IKKα pathway and enhanced ERK1/2 activity. Based on this mechanism,
curcumin has potential as a chemosensitizer for
carboplatin in the treatment of patients with NSCLC.