title: 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.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Lang
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Xiuchao
authors.initials: X
authors.lastname: Wang
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Dong
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Chungen
authors.initials: C
authors.lastname: Lan
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Jihui
authors.initials: J
authors.lastname: Hao
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Chongbiao
authors.initials: C
authors.lastname: Huang
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Public Health, Tianjin Medical University, Tianjin, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Yu
authors.affiliation: 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Tumor Biology and Comprehensive Melanoma Research Center, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
authors.forename: Shengyu
authors.initials: S
authors.lastname: Yang
authors.affiliation: National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. Electronic address: renhe@tjmuch.com.
authors.forename: He
authors.initials: H
authors.lastname: Ren
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001665:Binding Sites; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009150:Mustard Compounds / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010666:Phenylpropionates / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000084622:Sestrins
chemical_list: D000077237:Arsenic Trioxide; D001152:Arsenicals; D000071161:Forkhead Box Protein O1; D006360:Heat-Shock Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009150:Mustard Compounds; D010087:Oxides; D010666:Phenylpropionates; D017382:Reactive Oxygen Species; C492908:2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide; C085126:FOXO1 protein, human; C497442:HIF1A protein, human; C485523:SESN3 protein, human; D000084622:Sestrins
keywords: Arsenic trioxide; Combination treatment; PX-478; Pancreatic ductal adenocarcinoma; Reactive oxygen species