T63, a new 4-arylidene curcumin analogue, induces cell cycle arrest and apoptosis through activation of the reactive oxygen species-FOXO3a pathway in lung cancer cells.

Curcumin (diferuloylmethane) is a natural polyphenol product of the plant Curcuma longa and has a diversity of antitumor activities. T63, a new 4-arylidene curcumin analogue, was reported to inhibit proliferation of lung cancer cells. However, its precise molecular antitumor mechanisms have not been well elucidated. Here, we showed that T63 could significantly inhibit the proliferation of A549 and H460 human lung cell lines via induction of G0/G1 cell cycle arrest and apoptosis. We found that the reactive oxygen species (ROS)-activated FOXO3a cascade plays a central role in T63-induced cell proliferation inhibition. Mechanistically, enhancement of ROS production by T63 induced FOXO3a expression and nuclear translocation through activation of p38MAPK and inhibition of AKT, subsequently elevating the expression of FOXO3a target genes, including p21, p27, and Bim, and then increased the levels of activated caspase-3 and decreased the levels of cyclin D1. Moreover, the antioxidant N-acetylcysteine markedly blocked the above effects, and small interfering RNA-mediated knockdown of FOXO3a also significantly decreased T63-induced cell cycle arrest and apoptosis. In vivo experiments showed that T63 significantly suppressed the growth of A549 lung cancer xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. These data indicated that the novel curcumin analogue T63 is a potent antitumor agent that induces cell cycle arrest and apoptosis and has significant therapeutic potential for lung cancer.