A perylene derivative regulates HIF-1伪 and Stat3 signaling pathways
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- 作者：Han Chen ; Yongli Guan ; Gu Yuan ; Qiang Zhang ; Naijie Jing
- 关键词：HIF-1 ; hypoxia-inducible factor-1 ; STAT ; signal transducer and activator of transcription ; SRC ; v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog ; JAK ; Janus kinase ; ERK ; extracellular signal-regulated protein kinases ; AKT ; serine/threonine protein kinase ; BCL-2 ; B-cell lymphoma 2 ; VEGF ; vascular endothelial growth factor ; GLUT1 ; glucose transporter 1 ; SPR ; surface plasmon resonance
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：15 February, 2014
- 年：2014
- 卷：22
- 期：4
- 页码：1496-1505
- 全文大小：3552 K
文摘
It is becoming increasingly evident that improving the cure rate of many cancers will require treatment regimens hit more than one validated tumor targets. Developing an anti-cancer agent that targets two oncoproteins simultaneously is a promising strategy for accomplishing this goal. It would be expected to promote drug efficacy, reduce therapy-resistant without introducing additional toxic side effects. HIF-1伪 is a key regulator of the cellular response to hypoxia and is involved in tumor angiogenesis and cancer cell survival, glucose metabolism, and invasion. Stat3 has several oncogenic functions, including suppression of anti-tumor immune responses and promotion of inflammation. Recently, we have identified the perylene derivative, TEL03, as a dual inhibitor that targets both HIF-1伪 and Stat3. TEL03 blocks the expression of both HIF-1伪 and Stat3, regulated oncogenes (e.g., Bcl-2, VEGF, Glut1, and others) in cancer cells, and induces cancer cell apoptosis. The results demonstrated that: (i) TEL03 blocks Stat3 phosphorylation, and inhibits Stat3 transcriptional activity; and (ii) interferes the binding of HIF-1伪 to p300/CBP inducing its degradation by proteasomes under hypoxic conditions. Our in vivo tests showed that as a dual inhibitor, TEL03 dramatically inhibited tumor growth, and provided the evidence that targeting both HIF-1伪 and Stat3 simultaneously could be a promising strategy for breast and pancreatic cancer therapies.