A perylene derivative regulates HIF-1α and Stat3 signaling pathways

作者：Chen, Han^*; Guan, Yongli; Yuan, Gu; Zhang, Qiang; Jing, Naijie

来源：Bioorganic & Medicinal Chemistry, 2014, 22(4): 1496-1505.

DOI：10.1016/j.bmc.2013.10.018

• Stat3: the signal transducer and activator of transcription 3
• HIF-1 alpha: hypoxia-inducible factor-1 alpha
• Pancreatic cancer therapy
• Breast cancer therapy
• TEL03: a dual inhibitor of HIF-1 alpha and Stat3

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 alpha 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 alpha and Stat3. TEL03 blocks the expression of both HIF-1 alpha 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 alpha 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 alpha and Stat3 simultaneously could be a promising strategy for breast and pancreatic cancer therapies.

• 出版日期2014-2-15
• 单位北京大学