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

Abstract

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.

• Authors: Xinrui Zhang, Mengya Wang, Shanshan Teng, Di Wang, Xin Li, Xiaofeng Wang, Weiwei Liao, Di Wang
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 293 Pg. 61-69 (Sep 25 2018) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 30055129 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Chalcones
• Heat-Shock Proteins
• NF-E2-Related Factor 2
• Reactive Oxygen Species
• bcl-2-Associated X Protein
• Catalase
• Heme Oxygenase-1
• Caspases

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Caspases (metabolism)
• Catalase (metabolism)
• Cell Movement (drug effects)
• Chalcones (chemistry, pharmacology)
• Heat-Shock Proteins (metabolism)
• Heme Oxygenase-1 (metabolism)
• Hep G2 Cells
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Nude
• Mitochondria (drug effects, metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects)
• Reactive Oxygen Species (metabolism)
• bcl-2-Associated X Protein (metabolism)