Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan.
Exp Cell Res. 2012 Aug 1;318(13):1554-63. doi: 10.1016/j.yexcr.2012.03.013. Epub 2012 Mar 24.
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.
肿瘤缺氧被认为是一个潜在的治疗靶点，因为缺氧是实体瘤的一个共同特征，与它们的恶性表型有关。在本研究中，我们研究了一种新型低氧细胞毒素 3-[2-羟乙基（甲基）氨基]-2-喹喔啉甲腈 1,4-二氧化物（TX-2098）对缺氧诱导因子-1α（HIF-1α）表达的抑制作用，进而对胰腺癌细胞血管内皮细胞生长因子（VEGF）表达的抗肿瘤作用。采用 WST-8 法检测 TX-2098 在缺氧条件下对各种人胰腺癌细胞系的抗肿瘤作用。通过 ELISA 法检测细胞无血清上清液中诱导的 VEGF 蛋白。此外，用 TX-2098 治疗皮下（s.c.）或原位植入人 SUIT-2 的裸鼠。在治疗组与对照组之间评估肿瘤体积、存活和 HIF-1 及其相关分子的表达。在体外，TX-2098 抑制了各种胰腺癌细胞系的增殖。在 s.c.模型中，用胰腺癌细胞注射并用 TX-2098 治疗的裸鼠肿瘤体积明显减小（P<0.01 与对照组相比）。定量实时逆转录-PCR 分析显示，TX-2098 显著抑制了 HIF-1 相关分子、VEGF、葡萄糖转运蛋白 1 和醛缩酶 A 的 mRNA 表达（P<0.01 与对照组相比）。这些治疗还延长了原位模型中的存活时间。这些结果表明，TX-2098 在胰腺癌细胞中的作用可能与 VEGF 和 HIF-1 靶向分子的表达有关。
