Synergistic Anti-Cancer Activities of Curcumin Derivative CU17 Combined with Gemcitabine Against A549 Non-Small-Cell Lung Cancer Cells

Recently, the curcumin derivative CU17 possessing HDAC inhibitory activity has been shown to synergistically enhance the anti-proliferative activity of Gem against lung cancer cells. Nevertheless, the mechanism(s) underlying the synergistic anti-cancer effect remains to be investigated. This study aimed to investigate the mechanisms that underpin the anti-cancer activity of the combined Gem and CU17 against NSCLC A549 cells both in vitro and in mouse xenograft models. CU17 was successfully synthesized and subsequently investigated for its combination effects with Gem on inductions of cell cycle arrest and apoptosis in A549 cells. The combination treatment substantially decreased cell survival through S phase prolongation and G2/M phase cell cycle arrest via up-regulating the expressions of p21 and p53 proteins. Additionally, CU17 potentiated the apoptotic effect of Gem in A549 cells by increasing the Bax/Bcl-2 ratio. The co-treatment resulted in an up-regulation of pERK1/2 and Ac-H3 expression. An in vivo study demonstrated that CU17 significantly improved the anti-cancer effect of Gem in nude mice utilizing A549 cell xenografts. The hematoxylin and eosin (H&E) staining results indicated that CU17 decreased the toxicity of Gem to the liver, kidneys, and spleen. Overall, CU17 enhanced the effectiveness of Gem while decreasing its toxicity. This compound shows promise as a chemosensitizer for NSCLC treatment with Gem.