title: Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells.
abstract: Chondrosarcomas are malignant bone tumors that produce cartilaginous matrix. Mutations in isocitrate dehydrogenase enzymes (IDH1/2) were recently described in several cancers including chondrosarcomas. The IDH1 inhibitor AGI-5198 abrogates the ability of mutant IDH1 to produce the oncometabolite D-2 hydroxyglutarate (D-2HG) in gliomas. We sought to determine if treatment with AGI-5198 would similarly inhibit tumorigenic activity and D-2HG production in IDH1-mutant human chondrosarcoma cells. Two human chondrosarcoma cell lines, JJ012 and HT1080 with endogenous IDH1 mutations and a human chondrocyte cell line C28 with wild type IDH1 were employed in our study. Mutation analysis of IDH was performed by PCR-based DNA sequencing, and D-2HG was detected using tandem mass spectrometry. We confirmed that JJ012 and HT1080 harbor IDH1 R132G and R132C mutation, respectively, while C28 has no mutation. D-2HG was detectable in cell pellets and media of JJ012 and HT1080 cells, as well as plasma and urine from an IDH-mutant chondrosarcoma patient, which decreased after tumor resection. AGI-5198 treatment decreased D-2HG levels in JJ012 and HT1080 cells in a dose-dependent manner, and dramatically inhibited colony formation and migration, interrupted cell cycling, and induced apoptosis. In conclusion, our study demonstrates anti-tumor activity of a mutant IDH1 inhibitor in human chondrosarcoma cell lines, and suggests that D-2HG is a potential biomarker for IDH mutations in chondrosarcoma cells. Thus, clinical trials of mutant IDH inhibitors are warranted for patients with IDH-mutant chondrosarcomas.
authors.affiliation: Division of Hematology and Oncology/Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Luyuan
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Hematology and Oncology/Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Paz
authors.affiliation: Division of Hematology and Oncology/Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Breelyn A
authors.initials: BA
authors.lastname: Wilky
authors.affiliation: Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Britt
authors.initials: B
authors.lastname: Johnson
authors.affiliation: Department of Orthopaedic Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Karina
authors.initials: K
authors.lastname: Galoian
authors.affiliation: Department of Pathology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosenberg
authors.affiliation: Division of Hematology and Oncology/Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Hu
authors.affiliation: Division of Hematology and Oncology/Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Tinoco
authors.affiliation: Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Olaf
authors.initials: O
authors.lastname: Bodamer
authors.affiliation: Division of Hematology and Oncology/Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America; Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
mesh_terms: D017209:Apoptosis; D044482:Benzeneacetamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D002813:Chondrosarcoma / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense
chemical_list: C581156:AGI-5198; D044482:Benzeneacetamides; D004791:Enzyme Inhibitors; D005977:Glutarates; D007093:Imidazoles; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human