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

Exp Cell Res. 2012 Aug 1;318(13):1554-63. doi: 10.1016/j.yexcr.2012.03.013. Epub 2012 Mar 24.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclic N-Oxides / pharmacology*
  • Cytotoxins / pharmacology*
  • Female
  • Fructose-Bisphosphate Aldolase / genetics
  • Fructose-Bisphosphate Aldolase / metabolism
  • Gene Expression / drug effects
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Humans
  • Hypoxia / drug therapy
  • Hypoxia / genetics
  • Hypoxia / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Mice
  • Mice, Nude
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Quinoxalines / pharmacology*
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Cyclic N-Oxides
  • Cytotoxins
  • Glucose Transporter Type 1
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Quinoxalines
  • SLC2A1 protein, human
  • TX-2098
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Fructose-Bisphosphate Aldolase