Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related

Toxicology
Kevin M BeggsRobert A Roth

Abstract

Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of hepatocytes in vitro that was associated with prolonged activation of c-Jun N-terminal kinase (JNK), activation of caspases 9 and 3, and DNA damage. The purpose of this study was to explore further the mechanism by which TVX interacts with TNF to cause cytotoxicity. Treatment with TVX caused cell cycle arrest, enhanced expression of p21 and impaired proliferation, but cell death only occurred after cotreatment with TVX and TNF. Cell death involved activation of extracellular signal-related kinase (ERK), which in turn activated caspase 3 and ataxia telangiectasia and Rad3-related (ATR), both of which contributed to cytotoxicity. Cotreatment of HepG2 cells with TVX and TNF caused double-strand breaks in DNA, and ERK contributed to this effect. Inhibition of caspase activity abolished the DNA strand breaks. The data suggest a complex interaction of TVX and TNF in which TVX causes replication stress, and the downstream effects are exacerbated by TNF, leading to hepatocellular death. These results raise...Continue Reading

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Citations

Sep 11, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Zhen RenLei Guo
Sep 6, 2018·Journal of Applied Toxicology : JAT·Weijia HanZhongping Duan
Jan 21, 2017·The Journal of Pharmacology and Experimental Therapeutics·Robert A RothPatricia E Ganey
Mar 17, 2020·International Journal of Toxicology·Kenneth L HastingsGary R Burleson
Apr 24, 2020·Expert Opinion on Drug Metabolism & Toxicology·Robert A Roth, Patricia E Ganey
Jun 22, 2017·Toxicological Sciences : an Official Journal of the Society of Toxicology·Sreenivasa C RamaiahgariStephen S Ferguson
Feb 9, 2020·Toxicology and Applied Pharmacology·Giulio GiustariniRaymond H H Pieters

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