Curcumin analog, WZ37, promotes G2/M arrest and apoptosis of HNSCC cells through Akt/mTOR inhibition

Abstract Head and neck squamous cell carcinoma (HNSCC) is a leading form of malignancy arising from the head and neck region. Existing conventional therapies are toxic and induce resistance to advanced HNSCC, therefore, new highly efficient therapeutic agents are urgently needed. The present study investigated the anti-cancer efficacy of WZ37, a curcumin analog, in HNSCC cell lines, and defined the mechanism of this activity. Results indicated that WZ37 inhibited proliferation of several HNSCC cell types by G2/M cycle arrest, promoted expression of a pro-apoptotic protein profile, and induced ROS-dependent mitochondrial injury and ER stress. Pre-treatment with NAC, an ROS scavenger, lowered the anti-cancer activity of WZ37 in HEP-2 cells. Long-term treatment of WZ37 (24 h) decreased Akt/mTOR phosphorylation which was accompanied by increased expression of BAD and PTEN. Moreover, co-treatment of WZ37 with MK-2206 (Akt inhibitor) promoted cancer cell apoptosis. Our findings indicated that the anti-cancer potential of WZ37 was attributed to ROS-dependent cell cycle arrest, mitochondrial injury, and ER stress, leading to apoptosis. The basis of the HNSCC cell apoptosis was through a mechanism of inhibition of the oxidant-sensitive Akt/mTOR pathway. We conclude that WZ37 can be a promising anti-cancer agent for the treatment of HNSCC.