Dikmen Z Gunnur, Gellert Ginelle C, Dogan Pakize, Yoon Heejeong, Lee Young Bok, Ahn Chang Ho, Shay Jerry W
Department of Biochemistry, Faculty of Medicine, University of Hacettepe, 06100 Sihhiye, Ankara, Turkey.
J Cell Biochem. 2008 Jun 1;104(3):985-94. doi: 10.1002/jcb.21681.
HIF-1alpha plays a major role in activating gene transcription and is important for maintaining homeostasis under hypoxic conditions. Since tumors are often in a hypoxic state, HIF-1alpha is a potential target for the development of novel cancer therapeutics. This study was performed to determine the antitumoral efficacy of an antisense HIF-1alpha inhibitor, RX-0047 on different human cancer cell lines (MDA-MB 231, HME50-T, PC-3, Panc-1 and A549) in vitro. A549 lung cancer and PC-3 prostate cancer cells containing a luciferase gene reporter were used for in vivo xenograft animal models. Progressive tumor development was quantified using live animal BLI (bioluminescence imaging) in addition to ex vivo imaging and histology. All cell lines tested were sensitive to inhibition of cell growth with 10 nM and higher ranges of RX-0047, additionally RX-0047 sensitizes cells to ionizing radiation treatments. Finally, RX-0047 (30 mg/kg) inhibited the formation of human lung metastasis in xenograft mouse models and reduced tumor size in flank models.
缺氧诱导因子-1α（HIF-1α）在激活基因转录中起主要作用，对在缺氧条件下维持体内平衡很重要。由于肿瘤常处于缺氧状态，HIF-1α是新型癌症治疗药物开发的潜在靶点。本研究旨在体外确定反义HIF-1α抑制剂RX-0047对不同人类癌细胞系（MDA-MB 231、HME50-T、PC-3、Panc-1和A549）的抗肿瘤疗效。含有荧光素酶基因报告基因的A549肺癌细胞和PC-3前列腺癌细胞用于体内异种移植动物模型。除了体外成像和组织学检查外，还使用活体动物生物发光成像（BLI）对肿瘤的进展进行定量。所有测试的细胞系对10 nM及更高浓度范围的RX-0047抑制细胞生长均敏感，此外，RX-0047使细胞对电离辐射治疗敏感。最后，RX-0047（30 mg/kg）在异种移植小鼠模型中抑制了人肺转移的形成，并减小了侧腹模型中的肿瘤大小。
