title: Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice.
abstract: Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) is frequently detected in osteosarcoma, and hence, may serve as a therapeutic target. In order to target STAT3, we tested two new STAT3 inhibitors, LLL12 and FLLL32. LLL12 and FLLL32 inhibit STAT3 phosphorylation and STAT3 downstream targets. LLL12 and FLLL32 also inhibit IL-6 induced STAT3 phosphorylation. The inhibition of STAT3 by LLL12 and FLLL32 resulted in the induction of apoptosis, reduction of plating efficiency, and migration in osteosarcoma cells. Furthermore, LLL12 and FLLL32 inhibited SJSA osteosarcoma cells and OS-33 tumor growth in murine xenografts. These results provide evidence that constitutive STAT3 signaling is required for osteosarcoma survival and migration in vitro and tumor growth in vivo. Blocking persistent STAT3 signaling by LLL12 and FLLL32 may be a novel therapeutic approach for osteosarcoma.
authors.affiliation: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.
authors.forename: Grace-Ifeyinwa
authors.initials: GI
authors.lastname: Onimoe
authors.forename: Aiguo
authors.initials: A
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Chang-Ching
authors.initials: CC
authors.lastname: Wei
authors.forename: Eric B
authors.initials: EB
authors.lastname: Schwartz
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhasin
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: James R
authors.initials: JR
authors.lastname: Fuchs
authors.forename: Pui-kai
authors.initials: PK
authors.lastname: Li
authors.forename: Peter
authors.initials: P
authors.lastname: Houghton
authors.forename: Amanda
authors.initials: A
authors.lastname: Termuhlen
authors.forename: Thomas
authors.initials: T
authors.lastname: Gross
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000880:Anthraquinones; D000970:Antineoplastic Agents; C548902:FLLL 32; D015850:Interleukin-6; C549232:LLL12 compound; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D003474:Curcumin