Naringin alleviates methotrexate-induced liver injury in male albino rats and enhances its antitumor efficacy in HepG2 cells

被引:39
作者
Elsawy, Hany [1 ,2 ]
Algefare, Abdulmohsen I. [3 ]
Alfwuaires, Manal [3 ]
Khalil, Mahmoud [4 ,5 ]
Elmenshawy, Omar M. [6 ]
Sedky, Azza [3 ,5 ]
Abdel-Moneim, Ashraf M. [3 ,5 ]
机构
[1] King Faisal Univ, Dept Chem, Fac Sci, Al Hasa, Saudi Arabia
[2] Tanta Univ, Dept Chem, Fac Sci, Tanta, Egypt
[3] King Faisal Univ, Dept Biol Sci, Fac Sci, Hofuf 31982, Al Ahsa, Egypt
[4] Beirut Arab Univ, Dept Biol Sci, Fac Sci, Beirut, Lebanon
[5] Alexandria Univ, Dept Zool, Fac Sci, Alexandria, Egypt
[6] Al Azhar Univ, Dept Zool, Fac Sci, Cairo, Egypt
关键词
NF-KAPPA-B; OXIDATIVE STRESS; INDUCED HEPATOTOXICITY; GROWTH-INHIBITION; UP-REGULATION; CANCER CELLS; IN-VITRO; APOPTOSIS; ACTIVATION; DAMAGE;
D O I
10.1042/BSR20193686
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Methotrexate (MTX) is an efficient chemotherapeutic and immunosuppressant drug, but the hepatotoxicity of MTX limits its clinical use. Naringin (Nar) is a flavonoid derived from Citrus paradise, and has been shown to possess several pharmacological activities, including free-radical scavenging and antioxidant properties. In the present study, we first tested the possible protective effects of multiple doses of Nar against MTX-induced acute hepatotoxicity in rats, and then we investigated the growth inhibition and apoptotic effects of MTX and/or Nar against the HepG2 hepatocarcinoma cell line. Our in vivo results showed that Nar significantly reduced MTX-induced increases in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin levels. Nar also reduced MTX-induced oxidative stress by significantly reducing liver malondialdehyde (MDA) and nitric oxide (NO) content and increasing superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH). In addition, Nar significantly counteracted MTX-induced increases in hepatic interleukin-6 and tumor necrosis factor-alpha (TNF-alpha). Further, Nar greatly protected hepatocyte ultrastructure against MTX-induced injury. In contrast, in vitro MTX and/or Nar treatment of HepG2 cells for 48 h exhibited a cytotoxic effect and induced apoptosis in a dose-dependent manner mediated by a significant increase in the Bax/Bcl-2 protein expression ratio. Noticeably, Nar potentiated the MTX effect on the Bax/Bcl-2 ratio. In conclusion, Nar decreased MTX-induced functional and ultrastructural liver damage in a tumor-free animal model. Also, our data introduce MTX and Nar as promising antiproliferative agents with a distinctive mode of action, inducing apoptosis in HepG2 tumor cells through activation of Bax and down-regulation of Bcl-2 protein expression.
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页数:12
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