Chalcone-Induced Apoptosis through Caspase-Dependent Intrinsic Pathways in Human Hepatocellular Carcinoma Cells.

Rodrigo Ramirez-Tagle,Felipe Simon,Carlos Escobar,Emanuel Jeldes,Ricardo Armisén,Ignacio Montorfano,Luis Pizarro,Cesar Echeverria,Valentina Romero,Vincenzo Borgna

doi:10.3390/ijms17020260

Abstract

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide. Chemoprevention of HCC can be achieved through the use of natural or synthetic compounds that reverse, suppress or prevent the development of cancer progression. In this study, we investigated the antiproliferative effects and the mechanism of action of two compounds, 2,3,4′-trimethoxy-2′-hydroxy-chalcone (CH1) and 3′-bromo-3,4-dimethoxy-chalcone (CH2), over human hepatoma cells (HepG2 and Huh-7) and cultured mouse hepatocytes (HepM). Cytotoxic effects were observed over the HepG2 and Huh-7, and no effects were observed over the HepM. For HepG2 cells, treated separately with each chalcone, typical apoptotic laddering and nuclear condensation were observed. Additionally, the caspases and Bcl-2 family proteins activation by using Western blotting and immunocytochemistry were studied. Caspase-8 was not activated, but caspase-3 and -9 were both activated by chalcones in HepG2 cells. Chalcones also induced reactive oxygen species (ROS) accumulation after 4, 8 and 24 h of treatment in HepG2 cells. These results suggest that apoptosis in HepG2 was induced through: (i) a caspase-dependent intrinsic pathway; and (ii) by alterations in the cellular levels of Bcl-2 family proteins, and also, that the chalcone moiety could be a potent candidate as novel anticancer agents acting on human hepatomas.

Highlights

Hepatocellular carcinoma (HCC) is one of the most commonly occurring cancers in the world [1]
Chalcones induced reactive oxygen species (ROS) accumulation after 4, 8 and 24 h of treatment in HepG2 cells. These results suggest that apoptosis in HepG2 was induced through: (i) a caspase-dependent intrinsic pathway; and (ii) by alterations in the cellular levels of Bcl-2 family proteins, and that the chalcone moiety could be a potent candidate as novel anticancer agents acting on human hepatomas
Our results indicate that the two chalcones mediate the apoptosis in HepG2 cells in an intrinsic, caspase-dependent pathway, and that they increase the presence of ROS

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of the most commonly occurring cancers in the world [1]. HCC is a relatively chemotherapy-resistant tumor mainly due to their heterogeneity and because of multidrug resistance phenotype’s development [3]. Hepatocellular carcinoma (HCC) is one of the few cancers with well-defined major risk factors [7,8]. Genotoxic stress-induced apoptotic cell death by chemotherapy remains the primary anticancer treatment. Despite the tremendous strides made in the development of targeted anticancer therapies, the prevalence of resistance to genotoxic drugs is still a major obstacle in the successful management of resistant and aggressive tumors [9,10,11]. Oxidative stress may contribute to cancer initiation through ROS-induced DNA damage [14]

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