Antiproliferative and apoptosis-inducing activity of curcumin against human gallbladder adenocarcinoma cells

Curcumin has potent antitumor activity against many types of human cancers. However, the inhibitory effects and possible mechanisms of curcumin on gallbladder cancer remains to be determined.

Using HAG-1 human gallbladder adenocarcinoma cells, we investigated the effects of curcumin on cell proliferation, apoptosis, cell-cycle perturbation, and signal proteins for survival, proliferation, and apoptosis.

Curcumin exhibited dose-dependent antitumor activity against HAG-1 cells, arresting the cells in G2/M phase, with progressive expansion of the apoptotic cell population. Upon curcumin treatment, AKT activation was substantially suppressed, with subsequent reduction of activities of mammalian target of rapamycin (mTOR) and its downstream molecules S6 kinase-1 (S6K1) and elF4E-binding protein-1 (4E-BP1), but constitutive activity of extracellular signal-regulated kinase (ERK1/2) was clearly enhanced. Curcumin reduced the expression and phosphorylation of anti-apoptotic Bcl-2, but did not affect the expressions of pro-apoptotic Bax and anti-apoptotic nuclear factor (NF-κB).

These results suggest that curcumin induces G2/M arrest and apoptosis through multiple mechanisms involving enhanced mitogen-activated protein (MAP) kinase activity, reduced AKT-mTOR activity, and reduced Bcl-2 function. These data provide a mechanistic rationale for the potential use of curcumin in the treatment of gallbladder cancer.