title: The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1α targeted gene expression.
abstract: Tumor hypoxia has been considered to be a potential therapeutic target, because hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. In the present study, we investigated the antitumor effect of a novel hypoxic cytotoxin, 3-[2-hydroxyethyl(methyl)amino]-2-quinoxalinecarbonitrile 1,4-dioxide (TX-2098) in inhibiting the expression of hypoxia inducible factor-1α (HIF-1α), and consequently vascular endothelial cell growth factor (VEGF) expression in pancreatic cancer. The antitumor effects of TX-2098 under hypoxia were tested against various human pancreatic cancer cell lines using WST-8 assay. VEGF protein induced pancreatic cancer was determined on cell-free supernatant by ELISA. Moreover, nude mice bearing subcutaneously (s.c.) or orthotopically implanted human SUIT-2 were treated with TX-2098. Tumor volume, survival and expression of HIF-1 and associated molecules were evaluated in treatment versus control groups. In vitro, TX-2098 inhibited the proliferation of various pancreatic cancer cell lines. In s.c model, tumors from nude mice injected with pancreatic cancer cells and treated with TX-2098 showed significant reductions in volume (P<0.01 versus control). Quantitative real-time reverse transcription-PCR analysis revealed that TX-2098 significantly inhibited mRNA expression of the HIF-1 associated molecules, VEGF, glucose transporter 1 and Aldolase A (P<0.01 versus control). These treatments also prolong the survival in orthotopic models. These results suggest that the effect of TX-2098 in pancreatic cancer might be correlated with the expression of VEGF and HIF-1 targeted molecules.
authors.affiliation: Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. hif.panc@gmail.com
authors.forename: Kotaro
authors.initials: K
authors.lastname: Miyake
authors.forename: Masanori
authors.initials: M
authors.lastname: Nishioka
authors.forename: Satoru
authors.initials: S
authors.lastname: Imura
authors.forename: Erdenebulgan
authors.initials: E
authors.lastname: Batmunkh
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Uto
authors.forename: Hideko
authors.initials: H
authors.lastname: Nagasawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Shimada
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D003603:Cytotoxins / Q000494:pharmacology*; D005260:Female; D005634:Fructose-Bisphosphate Aldolase / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011810:Quinoxalines / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D003603:Cytotoxins; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011810:Quinoxalines; C495677:SLC2A1 protein, human; C574489:TX-2098; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D005634:Fructose-Bisphosphate Aldolase