title: Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells.
abstract: The constitutive activation of signal transducer and activator of transcription 3 (STAT3) is frequently detected in most types of human cancer where it plays important roles in survival, drug resistance, angiogenesis, and other functions. Targeting constitutive STAT3 signaling is thus an attractive therapeutic approach for these cancers. We have recently developed novel small-molecule STAT3 inhibitors, known as FLLL31 and FLLL32, which are derived from curcumin (the primary bioactive compound of turmeric). These compounds are designed to bind selectively to Janus kinase 2 and the STAT3 Src homology-2 domain, which serve crucial roles in STAT3 dimerization and signal transduction. Here we show that FLLL31 and FLLL32 are effective inhibitors of STAT3 phosphorylation, DNA-binding activity, and transactivation in vitro, leading to the impediment of multiple oncogenic processes and the induction of apoptosis in pancreatic and breast cancer cell lines. FLLL31 and FLLL32 also inhibit colony formation in soft agar and cell invasion and exhibit synergy with the anticancer drug doxorubicin against breast cancer cells. In addition, we show that FLLL32 can inhibit the induction of STAT3 phosphorylation by IFNalpha and interleukin-6 in breast cancer cells. We also show that administration of FLLL32 can inhibit tumor growth and vascularity in chicken embryo xenografts as well as substantially reduce tumor volumes in mouse xenografts. Our findings highlight the potential of these new compounds and their efficacy in targeting pancreatic and breast cancers that exhibit constitutive STAT3 signaling.
authors.affiliation: Department of Pediatrics, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43205, USA. lin.674@osu.edu
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Brian
authors.initials: B
authors.lastname: Hutzen
authors.forename: Mingxin
authors.initials: M
authors.lastname: Zuo
authors.forename: Sarah
authors.initials: S
authors.lastname: Ball
authors.forename: Stephanie
authors.initials: S
authors.lastname: Deangelis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Foust
authors.forename: Bulbul
authors.initials: B
authors.lastname: Pandit
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ihnat
authors.forename: Satyendra S
authors.initials: SS
authors.lastname: Shenoy
authors.forename: Samuel
authors.initials: S
authors.lastname: Kulp
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: James
authors.initials: J
authors.lastname: Fuchs
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D002642:Chick Embryo; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015536:Down-Regulation; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains
chemical_list: C548901:FLLL 31; C548902:FLLL 32; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D003474:Curcumin