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 overrelease 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 oxygenase1 (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.
[1]Jilin Univ, Sch Life Sci, Changchun 130012, Jilin, Peoples R China.
[2]Jilin Univ, Zhuhai Coll, Zhuhai 519041, Peoples R China.
[3]Jilin Univ, China Japan Union Hosp, Dept Stomatol, Changchun 130033, Jilin, Peoples R China.
[4]Jilin Univ, Coll Chem, Dept Organ Chem, Changchun 130012, Jilin, Peoples R China.
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