Arsenic trioxide plus PX-478 achieves effective treatment in pancreatic ductal adenocarcinoma.

Abstract

Arsenic trioxide (ATO) has been selected as a promising treatment not only in leukemia but also in solid tumors. Previous studies showed that the cytotoxicity of ATO mainly depends on the induction of reactive oxygen species. However, ATO has only achieved a modest effect in pancreatic ductal adenocarcinoma, suggesting that the existing radical scavenging proteins, such as hypoxia inducible factor-1, attenuate the effect. The goal of this study is to investigate the effect of combination treatment of ATO plus PX-478 (hypoxia-inducible factor-1 inhibitor) and its underlying mechanism. Here, we showed that PX-478 robustly strengthened the anti-growth and pro-apoptosis effect of ATO on Panc-1 and BxPC-3 pancreatic cancer cells in vitro. Meanwhile, in vivo mouse xenograft models also showed the synergistic effect of ATO plus PX-478 compared with any single agent. Further studies showed that the anti-tumor effect of ATO plus PX-478 was derived from the reactive oxygen species-induced apoptosis. We next confirmed that Hypoxia-inducible factor-1 cleared reactive oxygen species by its downstream target, forkhead box O transcription factors, and this effect may justify the strategy of ATO plus PX-478 in the treatment of pancreatic cancer.

• Authors: Mingxiao Lang, Xiuchao Wang, Hongwei Wang, Jie Dong, Chungen Lan, Jihui Hao, Chongbiao Huang, Xin Li, Ming Yu, Yanhui Yang, Shengyu Yang, He Ren
• Journal: Cancer letters (Cancer Lett) Vol. 378 Issue 2 Pg. 87-96 (08 10 2016) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 27212442 (Publication Type: Journal Article)
• Copyright: Copyright © 2016. Published by Elsevier Ireland Ltd.

Chemical References

• 2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
• Arsenicals
• FOXO1 protein, human
• Forkhead Box Protein O1
• HIF1A protein, human
• Heat-Shock Proteins
• Hypoxia-Inducible Factor 1, alpha Subunit
• Mustard Compounds
• Oxides
• Phenylpropionates
• Reactive Oxygen Species
• SESN3 protein, human
• Arsenic Trioxide

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Arsenic Trioxide
• Arsenicals (pharmacology)
• Binding Sites
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, metabolism, pathology)
• Cell Line
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Synergism
• Forkhead Box Protein O1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Heat-Shock Proteins (genetics, metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, genetics, metabolism)
• Mice, Nude
• Mustard Compounds (pharmacology)
• Oxidative Stress (drug effects)
• Oxides (pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, metabolism, pathology)
• Phenylpropionates (pharmacology)
• Promoter Regions, Genetic
• RNA Interference
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Time Factors
• Transcriptional Activation
• Transfection
• Xenograft Model Antitumor Assays