RRC ID 47420
Author Hoang NT, Kadonosono T, Kuchimaru T, Kizaka-Kondoh S.
Title Hypoxia-inducible factor-targeting prodrug TOP3 combined with gemcitabine or TS-1 improves pancreatic cancer survival in an orthotopic model.
Journal Cancer Sci
Abstract Pancreatic cancer is one of the most lethal digestive system cancers with a 5-year survival rate of 4-7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and TS-1, the current standard-of-care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia-inducible factor, a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers. TAT-ODD-procaspase-3 (TOP3) is a protein prodrug that is specifically processed and activated in hypoxia-inducible factor-active cells in cancers, leading to cell death. Here, we report combination therapies in which TOP3 was combined with gemcitabine or TS-1. As monotherapy, gemcitabine and TS-1 showed a limited effect on hypoxic and starved pancreatic cancer cells, whereas co-treatment with TOP3 successfully overcame this limitation in vitro. Furthermore, combination therapies of TOP3 with these drugs resulted in a significant improvement in survival of orthotopic pancreatic cancer models involving the human pancreatic cancer cell line SUIT-2. Overall, our study indicates that the combination of TOP3 with current chemotherapeutic drugs can significantly improve treatment outcome, offering a promising new therapeutic option for patients with pancreatic cancer.
Volume 107(8)
Pages 1151-8
Published 2016-8-1
DOI 10.1111/cas.12982
PMID 27270607
PMC PMC4982586
MeSH Animals Cell Line, Tumor Deoxycytidine / administration & dosage Deoxycytidine / analogs & derivatives* Deoxycytidine / pharmacology Fluorouracil / pharmacology Gemcitabine Humans Hypoxia-Inducible Factor 1 / antagonists & inhibitors* Male Mice Mice, Inbred BALB C Pancreatic Neoplasms / metabolism* Pancreatic Neoplasms / pathology* Prodrugs / metabolism* Prodrugs / pharmacology Recombinant Fusion Proteins / metabolism* Recombinant Fusion Proteins / pharmacology Silicates / administration & dosage Silicates / pharmacology* Survival Analysis Titanium / administration & dosage Titanium / pharmacology* Tumor Hypoxia Xenograft Model Antitumor Assays*
IF 4.966
Times Cited 9
DNA material pGEX-6P-3/GST-TAT-ODD/3-0-Casp3 (RDB14403) pEF/HRE-Fluc (RDB14404).