| Autor: |
Li X; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA. xiali@sdu.edu.cn.; School of Ocean, Shandong University, Weihai, China. xiali@sdu.edu.cn., Ma H; Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China., Li L; School of Ocean, Shandong University, Weihai, China., Chen Y; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA., Sun X; School of Ocean, Shandong University, Weihai, China., Dong Z; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA., Liu JY; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA. jliu2@iu.edu.; Department of Computer and Information Science, Indiana University-Purdue University, Indianapolis, IN, USA. jliu2@iu.edu., Zhu W; Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China. weimingzhu@ouc.edu.cn., Zhang JT; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA. jianzhan@iu.edu.; IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA. jianzhan@iu.edu. |
| Abstrakt: |
Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in malignant tumors and plays important roles in multiple aspects of cancer aggressiveness. Thus, targeting STAT3 promises to be an attractive strategy for the treatment of advanced metastatic tumors. Bisindolylmaleimide alkaloid (BMA) has been shown to have anti-cancer activities and was thought to suppress tumor cell growth by inhibiting protein kinase C. In this study, we show that a newly synthesized BMA analog, BMA097, is effective in suppressing tumor cell and xenograft growth and in inducing spontaneous apoptosis. We also provide evidence that BMA097 binds directly to the SH2 domain of STAT3 and inhibits STAT3 phosphorylation and activation, leading to reduced expression of STAT3 downstream target genes. Structure activity relationship analysis revealed that the hydroxymethyl group in the 2,5-dihydropyrrole-2,5-dione prohibits STAT3 inhibitory activity of BMA analogs. Altogether, we conclude that the synthetic BMA analogs may be developed as anti-cancer drugs by targeting and binding to the SH2 domain of STAT3 and inhibiting the STAT3 signaling pathway. |
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