The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1伪 targeted gene expression

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• 作者：Kotaro Miyake^a ; ^{hif.panc@gmail.com} ; Masanori Nishioka^a ; Satoru Imura^a ; Erdenebulgan Batmunkh^a ; Yoshihiro Uto^b ; Hideko Nagasawa^c ; Hitoshi Hori^b ; Mitsuo Shimada^a
• 关键词：TPZ ; Tirapazamine ; HIF-1 ; hypoxia inducible factor-1 ; VEGF ; vascular endothelial growth factor ; GLUT1 ; glucose transporter 1 ; ELISA ; enzyme-linked immunosorbent ; EPO ; erythropoietin ; GPI ; glucose phosphate isomerase ; GDEPT ; gene-directed enzyme prodrug th
• 刊名：Experimental Cell Research
• 出版年：2012
• 期刊代码：292_00144827
• 类别：med
• 出版时间：1 August, 2012
• 卷：318
• 期：13
• 页码：1554-1563
• 文件大小：870 K

摘要

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-1伪 (HIF-1伪), 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.