title: Synthesis of a novel adamantyl nitroxide derivative with potent anti-hepatoma activity in vitro and in vivo.
abstract: 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.
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical UniversityXi'an, Shaanxi 710032, China; College of Pharmacy, Shaanxi University of Chinese MedicineXianyang, Shaanxi 712046, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Bu
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Meng-Ying
authors.initials: MY
authors.lastname: Wei
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Wei-Wei
authors.initials: WW
authors.lastname: Li
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Min-Na
authors.initials: MN
authors.lastname: Yao
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Zhong-Ying
authors.initials: ZY
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Cheng-Tao
authors.initials: CT
authors.lastname: Lu
authors.affiliation: College of Pharmacy, Shaanxi University of Chinese Medicine Xianyang, Shaanxi 712046, China.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Li
authors.affiliation: College of Pharmacy, Shaanxi University of Chinese Medicine Xianyang, Shaanxi 712046, China.
authors.forename: Na-Ping
authors.initials: NP
authors.lastname: Hu
authors.affiliation: College of Pharmacy, Shaanxi University of Chinese Medicine Xianyang, Shaanxi 712046, China.
authors.forename: En-Hu
authors.initials: EH
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Guo-Dong
authors.initials: GD
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Ai-Dong
authors.initials: AD
authors.lastname: Wen
authors.affiliation: Department of Pharmacy, Xijing Hospital, Fourth Military Medical University Xi'an, Shaanxi 710032, China.
authors.forename: Xiao-He
authors.initials: XH
authors.lastname: Zhu
keywords: Adamantyl nitroxide derivative; anticancer; apoptosis; hepatoma; reactive oxygen species