PARP-1 inhibitor sensitizes arsenic trioxide in hepatocellular carcinoma cells via abrogation of G2/M checkpoint and suppression of DNA damage repair.

Abstract

Arsenic trioxide (ATO) is successfully used to treat hematological malignancies. However, the clinical application of the agent in solid tumors is largely limited by its dose-dependent toxicity which results from the high intrinsic resistance of the cancer cells. In this study, we firstly identified a series of sensitization effects of 4AN, a PARP-1 inhibitor, on human hepatocellular carcinoma cell line HepG2 to ATO treatment. We showed that treatment of HepG2 cells with 4AN promoted ATO-induced cell death in a synergistic manner. The ATO-sensitization by 4AN was associated with its effect on abrogation of ATO-induced G2/M checkpoint which impairs DNA damage repair and promotes cell apoptosis. Further analysis demonstrated that the ATO-induced G2/M checkpoint was closely related to a decrease in cyclin B1, a key G2/M mediator; whereas 4AN up-regulated the expression of cyclin B1 in ATO-treated cells, which may be at least partly responsible for its effect on abrogation of ATO-induced G2/M checkpoint. This was further supported by the result showing that down-regulation of cyclin B1 using siRNA could restore the G2/M checkpoint in cells co-treated with ATO and 4AN, thereby improving DNA damage repair and decreasing apoptosis. Our study indicates that the abrogation of G2/M checkpoint and the suppression of DNA damage repair contribute to ATO-sensitization by PARP-1 inhibitor in HepG2 cells, which provides a novel insight into the chemo-sensitization mechanism of PARP-1 inhibitor.

• Authors: Qingying Luo, Yang Li, Jianjun Deng, Zunzhen Zhang
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 226 Pg. 12-22 (Jan 25 2015) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 25499136 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Arsenicals
• Cyclin B1
• Enzyme Inhibitors
• Naphthalimides
• Oxides
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinolones
• 4-amino-1,8-naphthalimide
• 1-Naphthylamine
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Arsenic Trioxide

Topics

• 1-Naphthylamine (analogs & derivatives, pharmacology)
• Antineoplastic Agents (pharmacology)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Carcinoma, Hepatocellular (pathology)
• Cell Cycle Checkpoints (drug effects)
• Cyclin B1 (genetics, metabolism)
• DNA Damage
• DNA Repair (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Enzyme Inhibitors (pharmacology)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Hep G2 Cells
• Humans
• Liver Neoplasms (pathology)
• M Phase Cell Cycle Checkpoints (drug effects)
• Naphthalimides (pharmacology)
• Oxides (pharmacology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• Quinolones (pharmacology)
• Up-Regulation (drug effects)