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

Miyake, Kotaro ; Nishioka, Masanori ; Imura, Satoru ; Batmunkh, Erdenebulgan ; Uto, Yoshihiro ; Nagasawa, Hideko ; Hori, Hitoshi ; Shimada, Mitsuo

Experimental Cell Research, 01 August 2012, Vol.318(13) [Tạp chí có phản biện]

ISSN: 0014-4827 ; E-ISSN: 1090-2422 ; DOI: 10.1016/J.YEXCR.2012.03.013

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  • Nhan đề:
    The novel hypoxic cytotoxin, TX-2098 has antitumor effect in pancreatic cancer; possible mechanism through inhibiting VEGF and hypoxia inducible factor-1{alpha} targeted gene expression
  • Tác giả: Miyake, Kotaro ; Nishioka, Masanori ; Imura, Satoru ; Batmunkh, Erdenebulgan ; Uto, Yoshihiro ; Nagasawa, Hideko ; Hori, Hitoshi ; Shimada, Mitsuo
  • Chủ đề: 60 Applied LIFE Sciences ; Aldolases ; Anoxia ; Enzyme Immunoassay ; Erythropoietin ; Glucose ; Growth Factors ; Messenger-RNA ; Mice ; Neoplasms ; Pancreas ; Phosphates ; Polymerase Chain Reaction ; Therapy ; Biology
  • Là 1 phần của: Experimental Cell Research, 01 August 2012, Vol.318(13)
  • Mô tả: 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{alpha} (HIF-1{alpha}), 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. -- Highlights: Black-Right-Pointing-Pointer We designed and synthesized novel hypoxic cytoxin, TX-2098. Black-Right-Pointing-Pointer TX-2098 inhibited the proliferation of human pancreatic cancer cells than TPZ. Black-Right-Pointing-Pointer TX-2098 reduced VEGF protein level than TPZ. Black-Right-Pointing-Pointer TX-2098 inhibited mRNA expression of VEGF, GLUT1 and Aldolase A, not HIF-1{alpha}. Black-Right-Pointing-Pointer TX-2098 improved the survival in orthotopic SUIT-2 xenograft model.
  • Ngôn ngữ: English
  • Số nhận dạng: ISSN: 0014-4827 ; E-ISSN: 1090-2422 ; DOI: 10.1016/J.YEXCR.2012.03.013

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