title: The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells.
abstract: Tumors of the central nervous system represent a major source of cancer-related deaths, with medulloblastoma and glioblastoma being the most common malignant brain tumors in children and adults respectively. While significant advances in treatment have been made, with the 5-year survival rate for medulloblastoma at 70-80%, treating patients under 3 years of age still poses a problem due to the deleterious effects of radiation on the developing brain, and the median survival for patients with glioblastoma is only 15 months. The transcription factor, STAT3, has been found constitutively activated in a wide variety of cancers and in recent years it has become an attractive therapeutic target. We designed a non-peptide small molecule STAT3 inhibitor, LLL12, using structure-based design. LLL12 was able to inhibit STAT3 phosphorylation, decrease cell viability and induce apoptosis in medulloblastoma and glioblastoma cell lines with elevated levels of p-STAT3 (Y705). IC(50) values for LLL12 were found to be between 1.07 µM and 5.98 µM in the five cell lines expressing phosphorylated STAT3. STAT3 target genes were found to be downregulated and a decrease in STAT3 DNA binding was observed following LLL12 treatment, indicating that LLL12 is an effective STAT3 inhibitor. LLL12 was also able to inhibit colony formation, wound healing and decreased IL-6 and LIF secretion. Our results suggest that LLL12 is a potent STAT3 inhibitor and that it may be a potential therapeutic treatment for medulloblastoma and glioblastoma.
authors.affiliation: Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ball
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Pui-Kai
authors.initials: PK
authors.lastname: Li
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
mesh_terms: D000880:Anthraquinones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015850:Interleukin-6 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000880:Anthraquinones; D004273:DNA, Neoplasm; D015850:Interleukin-6; C549232:LLL12 compound; D053605:Leukemia Inhibitory Factor; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D013449:Sulfonamides