Indolyl-chalcone derivatives induce hepatocellular carcinoma cells apoptosis through oxidative stress related mitochondrial pathway in vitro and in vivo

• Published in: Chemico-biological interactions Vol. 293; pp. 61 - 69
• Main Authors: Zhang, Xinrui, Wang, Mengya, Teng, Shanshan, Wang, Di, Li, Xin, Wang, Xiaofeng, Liao, Weiwei
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 25.09.2018
• Subjects: Apoptosis; Hepatocellular carcinoma; Indolyl-chalcone derivatives; Mitochondria; Oxidative stress; Bcl-2; Oxidative stress; PON2; HO; Hepatocellular carcinoma; XIAP; HTRA2; DMEM; LDH; Mitochondria; Bcl-XL; Nrf2; FBS; IAPs; Hsp; DR5; HCC; Cyt C; H&E staining; MMP; Indolyl-chalcone derivatives; FasL; ROS; Bax; Keap1; Apoptosis
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2018.07.025

A facile method of assembling oxindole and phthalide units through a Lewis based catalyzed allylic alkylation reaction of Morita–Baylis–Hillman carbonates of isatins and 3-cyanophthalides was recently developed. The method efficiently delivers a hybrid of 3,3′-disubstituted oxindole with a valuable phthalide pharmacophore. In the present study, we proved the deleterious effects of 5h2c, a screened synthesis compound, against hepatocellular carcinoma (HCC) in both in vitro and in vivo models. 5h2c strongly decreased cell viability, caused over-release of lactate dehydrogenase, inhibited cell migration, and enhanced the apoptosis rate in HepG2 and PLC/PRF/5 cells. 5h2c led to an increase in intracellular reactive oxygen species levels and a decrease in mitochondrial membrane potential. In HepG2-and PLC/PRF/5-xenograft tumor mouse models, treatment with 5h2c inhibited tumor growth without affecting the animals' bodyweight or organ functions. Proteome profiling of tumor tissues after 24-h exposure to 5h2c showed significantly enhanced expression levels of Bcl-2 associated X protein, cleaved caspase −3, −8, and −9, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), heme oxygenase-2, paraoxonase 2, catalase, and factor associated suicide ligand, and reduced the expression levels of B-cell lymphoma-2, B-cell lymphoma-extra large, heat shock protein 27, heat shock protein 60, and heat shock protein 70 in HepG2 and PLC/PRF/5 cells. All of our data confirmed that oxidative stress-mediated mitochondrial apoptosis (especially the Nrf-2/HO-1 pathway) is responsible for 5h2c-induced HCC damage. •5h2c is a compound of 3,3′-disubstituted oxindole with a phthalide pharmacophore.•5h2c induces apoptosis in hepatocellular carcinoma cells.•5h2c inhibited the growth of HepG2-and PLC/PRF/5-xenografted tumor in mice.•5h2c-induced apoptosis via oxidative stress-mediated mitochondrial function.•5h2c promotes apoptosis of HCC cells through Nrf-2/HO-1 pathway.