Cytotoxicity, Oxidative Stress, Cell Cycle Arrest, and Mitochondrial Apoptosis after Combined Treatment of Hepatocarcinoma Cells with Maleic Anhydride Derivatives and Quercetin.

Gabriela Carrasco-Torres,Saúl Villa-Treviño,Erik Andrade-Jorge,José Guadalupe Trujillo-Ferrara,Verónica Rocío Vásquez-Garzón,Rafael Baltiérrez-Hoyos

doi:10.1155/2017/2734976

Abstract

The inflammatory condition of malignant tumors continually exposes cancer cells to reactive oxygen species, an oxidizing condition that leads to the activation of the antioxidant defense system. A similar activation occurs with glutathione production. This oxidant condition enables tumor cells to maintain the energy required for growth, proliferation, and evasion of cell death. The objective of the present study was to determine the effect on hepatocellular carcinoma cells of a combination treatment with maleic anhydride derivatives (prooxidants) and quercetin (an antioxidant). The results show that the combination of a prooxidant/antioxidant had a cytotoxic effect on HuH7 and HepG2 liver cancer cells, but not on either of two normal human epithelial cell lines or on primary hepatocytes. The combination treatment triggered apoptosis in hepatocellular carcinoma cells by activating the intrinsic pathway and causing S phase arrest during cell cycle progression. There is also clear evidence of a modification in cytoskeletal actin and nucleus morphology at 24 and 48 h posttreatment. Thus, the current data suggest that the combination of two anticarcinogenic drugs, a prooxidant followed by an antioxidant, can be further explored for antitumor potential as a new treatment strategy.

Highlights

The increase in the growth, proliferation, and survival of cancer cells is due to genetic and epigenetic changes that result in the modification of hundreds of genes that induce aberrations in multiple pathways
After completion of the synthesis of maleic anhydride derivatives, they were identified using infrared spectroscopy and 1H nuclear magnetic resonance spectrometry, where the displacements exhibited a clear correspondence between the spectra and the composition and structure of the molecules, indicating a purity of 99%: C1, IR (ATR, cm-1) ύ: 3281.6 (NH), 1702.91 (C=O), 2800 (C-H, aromatic), C=C (1625.5) and 1H NMR (CDCl3, 400 MHz) δ 10.80 (s, H-NH), 8.30 (s, H-6), 7.97 (s, H-2′), 7.97 (s, H-4′), 6.32, 6.42, C2, IR (ATR, cm-1) ύ: 1722.8 (C=O), 3100 (CH, aromatic), C=C (1600) and 1H NMR (CDCl3, 400 MHz) δ 7.66 (s, H-6), 7.99 (s, H-2′), 7.99 (s, H-4′), 7.59 (s, H-3), 7.59 (s, H-4)
GSH has a higher chemical potential, while the maleic anhydride derivatives have lower chemical potential. These results enabled us to predict that the electrons flow from GSH to α, β-unsaturated compounds, which is confirmed by the donor and acceptor potential where the electron flow occurs

Summary

Introduction

The increase in the growth, proliferation, and survival of cancer cells is due to genetic and epigenetic changes that result in the modification of hundreds of genes that induce aberrations in multiple pathways. One of these alterations includes the reprogramming of metabolism due to the requirement of high levels of energy, nucleotides, amino acids, and lipids for rapid cell growth and proliferation [1]. An oncogenic transcription factor, regulates intracellular stress and plays a key role in the environmental control of the abundant cellular antioxidant systems responsible for GSH production [7]. Excessive ROS production can affect cancer cells, resulting in cell cycle arrest and apoptosis [8]

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