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Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells.
Food Chem Toxicol. 2015 Jan; 75:173-86.FC

Abstract

Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial activities, has been shown to be genotoxic and potentially carcinogenic in several types of cells. However, the proper molecular mechanisms of FZD toxicity remain unclear. This study was aimed to explore the effect of FZD on apoptosis in HepG2 cells and uncover signaling pathway underlying the cytotoxicity of FZD. The results showed that FZD induced apoptosis in HepG2 cells in a dose-dependent manner characterized by nuclei morphology changes, cell membrane phosphatidylserine translocation, poly (ADP-ribose) polymerase (PARP) cleavage and a cascade activation of caspase-9 and -3. FZD could enhance reactive oxygen species (ROS) generation, up-regulate Bax/Bcl-2 ratio, disrupt mitochondrial membrane potential (MMP) and subsequently cause cytochrome c release. Both ROS scavenger (N-acetyl cysteine, NAC) and caspase inhibitors suppressed FZD-induced apoptosis. Furthermore, NAC attenuated FZD-induced ROS generation and mitochondrial dysfunction. Meanwhile, FZD treatment inhibited both the activation and expression of Akt, and PI3K/Akt inhibitor LY294002 promoted FZD-induced apoptosis. On the contrary, PI3K/Akt activator insulin-like growth factor-1 (IGF-1) attenuated lethality of FZD in HepG2 cells. In conclusion, it is first demonstrated that FZD-induced apoptosis in HepG2 cells might be mediated through ROS-dependent mitochondrial signaling pathway and involves PI3K/Akt signaling.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China.Department of Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Yuanmingyuan West Road No. 2, Beijing, Haidian District 100193, China. Electronic address: xiaoxl@cau.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25434308

Citation

Deng, Sijun, et al. "Furazolidone Induces Apoptosis Through Activating Reactive Oxygen Species-dependent Mitochondrial Signaling Pathway and Suppressing PI3K/Akt Signaling Pathway in HepG2 Cells." Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, vol. 75, 2015, pp. 173-86.
Deng S, Tang S, Zhang S, et al. Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells. Food Chem Toxicol. 2015;75:173-86.
Deng, S., Tang, S., Zhang, S., Zhang, C., Wang, C., Zhou, Y., Dai, C., & Xiao, X. (2015). Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells. Food and Chemical Toxicology : an International Journal Published for the British Industrial Biological Research Association, 75, 173-86. https://doi.org/10.1016/j.fct.2014.11.019
Deng S, et al. Furazolidone Induces Apoptosis Through Activating Reactive Oxygen Species-dependent Mitochondrial Signaling Pathway and Suppressing PI3K/Akt Signaling Pathway in HepG2 Cells. Food Chem Toxicol. 2015;75:173-86. PubMed PMID: 25434308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Furazolidone induces apoptosis through activating reactive oxygen species-dependent mitochondrial signaling pathway and suppressing PI3K/Akt signaling pathway in HepG2 cells. AU - Deng,Sijun, AU - Tang,Shusheng, AU - Zhang,Shen, AU - Zhang,Chaoming, AU - Wang,Congcong, AU - Zhou,Yan, AU - Dai,Chongshan, AU - Xiao,Xilong, Y1 - 2014/11/27/ PY - 2014/07/12/received PY - 2014/10/30/revised PY - 2014/11/22/accepted PY - 2014/12/2/entrez PY - 2014/12/2/pubmed PY - 2015/10/6/medline KW - Apoptosis KW - Furazolidone KW - Mitochondrial dysfunction KW - PI3K/Akt KW - Reactive oxygen species SP - 173 EP - 86 JF - Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association JO - Food Chem Toxicol VL - 75 N2 - Furazolidone (FZD), a synthetic nitrofuran with a broad spectrum of antimicrobial activities, has been shown to be genotoxic and potentially carcinogenic in several types of cells. However, the proper molecular mechanisms of FZD toxicity remain unclear. This study was aimed to explore the effect of FZD on apoptosis in HepG2 cells and uncover signaling pathway underlying the cytotoxicity of FZD. The results showed that FZD induced apoptosis in HepG2 cells in a dose-dependent manner characterized by nuclei morphology changes, cell membrane phosphatidylserine translocation, poly (ADP-ribose) polymerase (PARP) cleavage and a cascade activation of caspase-9 and -3. FZD could enhance reactive oxygen species (ROS) generation, up-regulate Bax/Bcl-2 ratio, disrupt mitochondrial membrane potential (MMP) and subsequently cause cytochrome c release. Both ROS scavenger (N-acetyl cysteine, NAC) and caspase inhibitors suppressed FZD-induced apoptosis. Furthermore, NAC attenuated FZD-induced ROS generation and mitochondrial dysfunction. Meanwhile, FZD treatment inhibited both the activation and expression of Akt, and PI3K/Akt inhibitor LY294002 promoted FZD-induced apoptosis. On the contrary, PI3K/Akt activator insulin-like growth factor-1 (IGF-1) attenuated lethality of FZD in HepG2 cells. In conclusion, it is first demonstrated that FZD-induced apoptosis in HepG2 cells might be mediated through ROS-dependent mitochondrial signaling pathway and involves PI3K/Akt signaling. SN - 1873-6351 UR - https://www.unboundmedicine.com/medline/citation/25434308/Furazolidone_induces_apoptosis_through_activating_reactive_oxygen_species_dependent_mitochondrial_signaling_pathway_and_suppressing_PI3K/Akt_signaling_pathway_in_HepG2_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0278-6915(14)00488-8 DB - PRIME DP - Unbound Medicine ER -