Synthesis of a novel adamantyl nitroxide derivative with potent anti-hepatoma activity in vitro and in vivo

• Published in: American journal of cancer research Vol. 6; no. 6; pp. 1271 - 1286
• Main Authors: Sun, Jin, Wang, Shan, Bu, Wei, Wei, Meng-Ying, Li, Wei-Wei, Yao, Min-Na, Ma, Zhong-Ying, Lu, Cheng-Tao, Li, Hui-Hui, Hu, Na-Ping, Zhang, En-Hu, Yang, Guo-Dong, Wen, Ai-Dong, Zhu, Xiao-He
• Format: Journal Article
• Language: English
• Published: United States e-Century Publishing Corporation 01.01.2016
• Subjects: Original; apoptosis; Adamantyl nitroxide derivative; hepatoma; anticancer; reactive oxygen species
• ISSN: 2156-6976; 2156-6976

In this study, a novel adamantyl nitroxide derivative was synthesized and its antitumor activities in vitro and in vivo were investigated. The adamantyl nitroxide derivative 4 displayed a potent anticancer activity against all the tested human hepatoma cells, especially with IC50 of 68.1 μM in Bel-7404 cells, compared to the positive control 5-FU (IC50=607.7 μM). The significant inhibition of cell growth was also observed in xenograft mouse model, with low toxicity. Compound 4 suppressed the cell migration and invasion, induced the G2/M phase arrest. Further mechanistic studies revealed that compound 4 induced cell death, which was accompanied with damaging mitochondria, increasing the generation of intracellular reactive oxygen species, cleavages of caspase-9 and caspase-3, as well as activations of Bax and Bcl-2. These results confirmed that adamantyl nitroxide derivative exhibited selective antitumor activities via mitochondrial apoptosis pathway in Bel-7404 cells, and would be a potential anticancer agent for liver cancer.