A novel small molecule inhibits STAT3 phosphorylation and DNA binding activity and exhibits potent growth suppressive activity in human cancer cells

Molecular Cancer

Research

Don Benson¹  Gregory B Lesinski¹  Stephanie Deangelis²  Elizabeth Foust²  Li Lin³  Jiayuh Lin⁴  Jiagao Lü⁵  Dale Hoyt⁶  James Fuchs⁶  Chenglong Li⁶  Pui-Kai Li⁶  Eric B Schwartz⁶ 

[1] Department of Internal Medicine, The Ohio State University, 43210, Columbus, Ohio, USA;Department of Pediatrics, College of Medicine, The Ohio State University, 43205, Columbus, Ohio, USA;Department of Pediatrics, College of Medicine, The Ohio State University, 43205, Columbus, Ohio, USA;Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China;Department of Pediatrics, College of Medicine, The Ohio State University, 43205, Columbus, Ohio, USA;Experimental Therapeutics Program, The Ohio State University Comprehensive Cancer Center, The Ohio State University, 43210, Columbus, Ohio, USA;Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, China;Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 43210, Columbus, Ohio, USA;

关键词: Multiple Myeloma;    Curcumin;    Liver Cancer Cell;    SNU387 Cell;    Liver Cancer Cell Line;   

DOI  :  10.1186/1476-4598-9-217

 received in 2009-11-04, accepted in 2010-08-16,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundTargeting Signal Transducer and Activator of Transcription 3 (STAT3) signaling is an attractive therapeutic approach for most types of human cancers with constitutively activated STAT3. A novel small molecular STAT3 inhibitor, FLLL32 was specifically designed from dietary agent, curcumin to inhibit constitutive STAT3 signaling in multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells.ResultsFLLL32 was found to be a potent inhibitor of STAT3 phosphorylation, STAT3 DNA binding activity, and the expression of STAT3 downstream target genes in vitro, leading to the inhibition of cell proliferation as well as the induction of Caspase-3 and PARP cleavages in human multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cell lines. However, FLLL32 exhibited little inhibition on some tyrosine kinases containing SH2 or both SH2 and SH3 domains, and other protein and lipid kinases using a kinase profile assay. FLLL32 was also more potent than four previously reported JAK2 and STAT3 inhibitors as well as curcumin to inhibit cell viability in these cancer cells. Furthermore, FLLL32 selectively inhibited the induction of STAT3 phosphorylation by Interleukin-6 but not STAT1 phosphorylation by IFN-γ.ConclusionOur findings indicate that FLLL32 exhibits potent inhibitory activity to STAT3 and has potential for targeting multiple myeloma, glioblastoma, liver cancer, and colorectal cancer cells expressing constitutive STAT3 signaling.

【 授权许可】

CC BY   
© Lin et al; licensee BioMed Central Ltd. 2010