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.

Combinatorial Low Dose Arsenic Trioxide and Cisplatin Exacerbates Autophagy via AMPK/STAT3 Signaling on Targeting Head and Neck Cancer Initiating Cells

“…Studies have shown that ATO was an effective therapeutic agent in APL with 63.8 to 93% high remission rate and could prolong patients' survival rate (13). A number of studies also have revealed a pro-apoptotic activity of ATO in solid tumors, including breast cancer, gastric cancer, hepatocellular carcinomas and sarcoma (14)(15)(16)(17). Although ATO is able to improve the disease outcome, of note, ATO also introduces to common side effects such as gastrointestinal disorders, cough, fatigue, skin rash, myelosuppression and the most burden are the liver function failure and cardiac toxicity (18).…”

Collateral Sensitivity of Parthenolide via NF-κB and HIF-α Inhibition and Epigenetic Changes in Drug-Resistant Cancer Cell Lines

“…NF-κB activation is also correlated with the down-regulation of the pro-apoptotic proteins Bax and Bad (Cao et al, 2013). The activity of NF-κB in hematologic malignancies and different solid tumors has been associated with anti-cancer drug resistance (Prasad et al, 2010; Luo et al, 2015). Inhibition of NF-κB signaling represents an effective strategy to improve the effectiveness of conventional anti-tumor drugs (Longley and Johnston, 2005).…”

Inhibition of nicotinamide phosphoribosyltransferase and depletion of nicotinamide adenine dinucleotide contribute to arsenic trioxide suppression of oral squamous cell carcinoma

“…In this study, our findings showed that 2 μM ATO exhibited the similar cytotoxicity to 10 nM FK866 in both cancer cell lines. Most noticeably, the regimen of ATO-FK866 combination showed synergistic cytotoxicity even at very low concentration of 2 μM ATO (2–50 μM represents the ATO dosage used in clinics for cancer chemotherapy (32). Meanwhile, cell apoptosis was dramatically increased in both OSCC cell lines after treatment with ATO or ATO-FK866 combination, which underlines the mechanism of the inhibition of cell viability by ATO.…”