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The role of NF-κB in PARP-inhibitor-mediated sensitization and detoxification of arsenic trioxide in hepatocellular carcinoma cells.

Abstract
The therapeutic efficacy of arsenic trioxide (ATO) for treatments of solid tumors is restricted by its drug resistance and chemotoxicity. In this study, we investigated ATO sensitization and detoxification effect of the Poly (ADP ribose) polymerase-1 (PARP-1) inhibitor 4-Amino-1,8-naphthalimide (4AN) in the hepatocellular carcinoma cell line HepG2. We firstly reported that ATO treatment induced the activation of Nuclear factor of κB (NF-κB) and its downstream anti-apoptosis and pro-inflammatory effectors in a PARP-1-dependent manner and thus conferred HepG2 cells with ATO resistance and toxicity. 4AN significantly suppressed the ATO-induced NF-κB activation, which promotes the apoptotic response and alleviates the inflammatory reaction induced by ATO, resulting in sensitization and detoxification against ATO. We also demonstrated that the ATO-induced activation of PARP-1 and NF-κB was closely associated with the oxidative DNA damage mediated by the generated reactive oxygen species (ROS). Furthermore, the attenuation of ATO-induced ROS and the resulting oxidative DNA damage by N-acetyl-L-cysteine (NAC), a potent antioxidant, significantly reduced the activation of PARP-1 and NF-κB in ATO-treated cells. Our study provides novel insights into the mechanism of the PARP-1-mediated NF-κB signaling pathway in ATO resistance and toxicity in anticancer treatments. This study also highlights the application potential of PARP-1 inhibitors in ATO-based anti-cancer treatments and in prevention of NF-κB-mediated therapeutic resistance and toxicity.
AuthorsQingying Luo, Yang Li, Yanhao Lai, Zunzhen Zhang
JournalThe Journal of toxicological sciences (J Toxicol Sci) Vol. 40 Issue 3 Pg. 349-63 (Jun 2015) ISSN: 1880-3989 [Electronic] Japan
PMID25972196 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Antioxidants
  • Arsenicals
  • NF-kappa B
  • Naphthalimides
  • Oxides
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinolones
  • Reactive Oxygen Species
  • 4-amino-1,8-naphthalimide
  • 1-Naphthylamine
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Arsenic Trioxide
  • Acetylcysteine
Topics
  • 1-Naphthylamine (analogs & derivatives, pharmacology)
  • Acetylcysteine (pharmacology)
  • Antineoplastic Agents (pharmacology)
  • Antioxidants (pharmacology)
  • Arsenic Trioxide
  • Arsenicals (pharmacology)
  • Carcinoma, Hepatocellular (metabolism, pathology)
  • DNA Damage
  • Hep G2 Cells
  • Humans
  • Inactivation, Metabolic (drug effects)
  • Liver Neoplasms (metabolism, pathology)
  • NF-kappa B (physiology)
  • Naphthalimides (pharmacology)
  • Oxidative Stress
  • Oxides (pharmacology)
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
  • Poly(ADP-ribose) Polymerases (metabolism)
  • Quinolones (pharmacology)
  • Reactive Oxygen Species

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