Liu Ling, Wang Dongmei, Wang Jiangang, Wang Shuying
Department of Pharmacy, Medical College, Henan University of Science and Technology, Luoyang, 471003, People's Republic of China.
Department of Pathogen Biology, Medical College, Henan University of Science and Technology, Luoyang, 471003, People's Republic of China.
J Biochem Mol Toxicol. 2016 Apr;30(4):192-9. doi: 10.1002/jbt.21778. Epub 2015 Nov 30.
Hepatocellular carcinoma is one of the most common and deadly forms of human malignancies. JS-K, O(2)-(2, 4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1, 2-diolate, has the ability to induce apoptosis of tumor cell lines. In the present study, JS-K inhibited the proliferation of HepG2 cells in a time- and concentration-dependent manner and significantly induced apoptosis. JS-K enhanced the ratio of Bax-to-Bcl-2, released of cytochrome c (Cyt c) from mitochondria and the activated caspase-9/3. JS-K caused an increasing cytosolic Ca(2+) and the loss of mitochondrial membrane potential. Carboxy-PTIO (a NO scavenger) and BAPTA-AM (an intracellular Ca(2+) chelator) significantly blocked an increasing cytosolic Ca(2+) in JS-K-induced HepG2 cells apoptosis, especially Carboxy-PTIO. Meanwhile, Carboxy-PTIO and BAPTA-AM treatment both attenuate JS-K-induced apoptosis through upregulation of Bcl-2, downregulation of Bax, reduction of Cyt c release from mitochondria to cytoplasm and inactivation of caspase-9/3. In summary, JS-K induced HepG2 cells apoptosis via Ca(2+)/caspase-3-mediated mitochondrial pathway.
肝细胞癌是人类最常见且致命的恶性肿瘤形式之一。JS-K，即O(2)-(2, 4-二硝基苯基) 1-[(4-乙氧羰基)哌嗪-1-基]重氮-1, 2-二醇盐，具有诱导肿瘤细胞系凋亡的能力。在本研究中，JS-K以时间和浓度依赖的方式抑制HepG2细胞的增殖，并显著诱导凋亡。JS-K提高了Bax与Bcl-2的比例，促进细胞色素c（Cyt c）从线粒体释放以及激活caspase-9/3。JS-K导致胞质Ca(2+)增加以及线粒体膜电位丧失。羧基-PTIO（一种NO清除剂）和BAPTA-AM（一种细胞内Ca(2+)螯合剂）显著阻断了JS-K诱导的HepG2细胞凋亡过程中胞质Ca(2+)的增加，尤其是羧基-PTIO。同时，羧基-PTIO和BAPTA-AM处理均通过上调Bcl-2、下调Bax、减少Cyt c从线粒体向细胞质的释放以及caspase-9/3的失活来减弱JS-K诱导的凋亡。总之，JS-K通过Ca(2+)/caspase-3介导的线粒体途径诱导HepG2细胞凋亡。
