Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma

Tiansuo Zhao; He Ren; Li Jia; Jing Chen; Wen Xin; Fan Yan; Jing Li; Xiuchao Wang; Song Gao; Dong Qian; Chongbiao Huang; Jihui Hao

doi:10.18632/oncotarget.2948

Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma

Oncotarget. 2015 Feb 10;6(4):2250-62. doi: 10.18632/oncotarget.2948.

Authors

Tiansuo Zhao¹, He Ren¹, Li Jia², Jing Chen¹, Wen Xin¹, Fan Yan¹, Jing Li¹, Xiuchao Wang¹, Song Gao¹, Dong Qian¹, Chongbiao Huang¹, Jihui Hao¹

Affiliations

¹ Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Department of Pancreatic Cancer, Tianjin, China.
² Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the worst prognoses among all the malignancies. Now, gemcitabine (Gem) is the first line chemotherapeutic drug for advanced pancreatic cancer. However, Gem is usually ineffective to the PDAC because of high degree of drug resistance. Hypoxia and immune suppressive milieu are the best-described hallmarks of PDAC; therefore, we investigated the impact of hypoxia inducible factor-1 (HIF-1) inhibitor, PX-478, in combination with Gem on the induction of immunogenic cell death (ICD). We verified that combined treatment with Gem/PX-478 significantly enhanced the anti-tumor effect and increased proportion of tumor infiltrating T-lymphocytes in Panc02-bearing immune-competent but not in immune-deficient mice. Vaccination using Panc02 cell line treated with single agent or in combination showed significant anti-tumor effects. Pancreatic cell lines treated with Gem and PX-478 can induce an increase in eIF2α phosphorylation was correlated with down-regulation of HIF-1α and elicited exposure of CRT and release of HMGB1 and ATP. Only co-treated cells induced DC maturation/phagocytosis and IFN-γ secretion by cytotoxic T lymphocytes. Altogether, combined treatment with Gem/PX-478 showed significantly inhibition on tumor growth and anti-tumor immunization. We propose that inhibition HIF-1α elicits Gem-induced immune response and eliminates PDAC cells by inducing ICD.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Animals
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Blotting, Western
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / metabolism
Carcinoma, Pancreatic Ductal / pathology
Cell Death / drug effects
Cell Death / immunology
Cell Line, Tumor
DNA-Binding Proteins / metabolism
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives*
Deoxycytidine / pharmacology
Drug Synergism
Gemcitabine
HMGB1 Protein / metabolism
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
Immunization
Mice, Inbred C57BL
Mice, Nude
Microscopy, Fluorescence
Mustard Compounds / administration & dosage
Mustard Compounds / pharmacology*
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology
Phenylpropionates / administration & dosage
Phenylpropionates / pharmacology*
Phosphorylation / drug effects
Survival Analysis
T-Lymphocytes / drug effects
T-Lymphocytes / immunology
T-Lymphocytes / metabolism
Transcription Factors / metabolism
Tumor Burden / drug effects
Tumor Burden / immunology

Substances

2-amino-3-(4'-N,N-bis(2-chloroethyl)amino)phenylpropionic acid N-oxide
DNA-Binding Proteins
Elf2 protein, mouse
HMGB1 Protein
Hypoxia-Inducible Factor 1, alpha Subunit
Mustard Compounds
Phenylpropionates
Transcription Factors
Deoxycytidine
Adenosine Triphosphate
Gemcitabine