Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells (Retracted article. See vol. 119, 2022)
Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells (Retracted article. See vol. 119, 2022)
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DOI：
10.1073/pnas.0812801106
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发表时间：
2009-02-17
影响因子：
11.1
通讯作者：
Semenza, Gregg L.
中科院分区：
文献类型：
--
作者：
Lee, KangAe;Qian, David Z.;Semenza, Gregg L.
使用基于细胞的报告基因测定，我们筛选了临床使用的药物库，并确定了蒽环类化疗药物阿霉素和柔红霉素作为低氧诱导因子1（HIF-1）介导的基因转录的有效抑制剂。这些药物通过阻断HIF-1与DNA的结合来抑制HIF-1。每日给予阿霉素或柔红霉素可有效抑制肿瘤异种移植物中HIF-1依赖性报告基因以及编码血管内皮生长因子、基质衍生因子1和干细胞因子的内源性HIF-1靶基因的转录。在携带前列腺癌异种移植物的SCID小鼠的外周血中，CXCR 4（+）/sca 1（+）、VEGFR 2（+）/CD 34（+）和VEGFR 2（+）/CD 117（+）骨髓来源的细胞增加，但在用阿霉素或柔红霉素治疗5天的荷瘤小鼠中没有增加，这显著减少了肿瘤血管形成。这些结果为蒽环类药物治疗的抗血管生成作用提供了分子基础，并对改进这些药物的使用以更有效地治疗人类癌症具有重要意义。
Using a cell-based reporter gene assay, we screened a library of drugs in clinical use and identified the anthracycline chemotherapeutic agents doxorubicin and daunorubicin as potent inhibitors of hypoxia-inducible factor 1 (HIF-1)-mediated gene transcription. These drugs inhibited HIF-1 by blocking its binding to DNA. Daily administration of doxorubicin or daunorubicin potently inhibited the transcription of a HIF-1-dependent reporter gene as well as endogenous HIF-1 target genes encoding vascular endothelial growth factor, stromal-derived factor 1, and stem cell factor in tumor xenografts. CXCR4(+)/sca1(+), VEGFR2(+)/CD34(+), and VEGFR2(+)/CD117(+) bone-marrow derived cells were increased in the peripheral blood of SCID mice bearing prostate cancer xenografts but not in tumor-bearing mice treated for 5 days with doxorubicin or daunorubicin, which dramatically reduced tumor vascularization. These results provide a molecular basis for the antiangiogenic effect of anthracycline therapy and have important implications for refining the use of these drugs to treat human cancer more effectively.