title: Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma.
abstract: While STAT3 has been validated as a target for treatment of many cancers, including head and neck squamous cell carcinoma (HNSCC), a STAT3 inhibitor is yet to enter the clinic. We used the scaffold of C188, a small-molecule STAT3 inhibitor previously identified by us, in a hit-to-lead program to identify C188-9. C188-9 binds to STAT3 with high affinity and represents a substantial improvement over C188 in its ability to inhibit STAT3 binding to its pY-peptide ligand, to inhibit cytokine-stimulated pSTAT3, to reduce constitutive pSTAT3 activity in multiple HNSCC cell lines, and to inhibit anchorage dependent and independent growth of these cells. In addition, treatment of nude mice bearing xenografts of UM-SCC-17B, a radioresistant HNSCC line, with C188-9, but not C188, prevented tumor xenograft growth. C188-9 treatment modulated many STAT3-regulated genes involved in oncogenesis and radioresistance, as well as radioresistance genes regulated by STAT1, due to its potent activity against STAT1, in addition to STAT3. C188-9 was well tolerated in mice, showed good oral bioavailability, and was concentrated in tumors. Thus, C188-9, either alone or in combination with radiotherapy, has potential for use in treating HNSCC tumors that demonstrate increased STAT3 and/or STAT1 activation.
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Uddalak
authors.initials: U
authors.lastname: Bharadwaj
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: T Kris
authors.initials: TK
authors.lastname: Eckols
authors.affiliation: The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, China.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Moses M
authors.initials: MM
authors.lastname: Kasembeli
authors.affiliation: Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Makoto
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Medicine, Division of Biostatistics, Dan L. Duncan Cancer Center, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Qianxing
authors.initials: Q
authors.lastname: Mo
authors.affiliation: Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
authors.affiliation: Department of Infectious Disease, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009284:Naphthols / Q000138:chemical synthesis / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D000970:Antineoplastic Agents; D009284:Naphthols; D050796:STAT3 Transcription Factor; D013449:Sulfonamides; C494086:STAT3 protein, human; C000625861:C188-9 compound; D000096926:Benzenesulfonamides
keywords: C188-9; HNSCC; STAT3; cancer; small molecule