Treatment with a Small Molecule Mutant IDH1 Inhibitor Suppresses Tumorigenic Activity and Decreases Production of the Oncometabolite 2-Hydroxyglutarate in Human Chondrosarcoma Cells

• Published in: PloS one Vol. 10; no. 9; p. e0133813
• Main Authors: Li, Luyuan, Paz, Ana C, Wilky, Breelyn A, Johnson, Britt, Galoian, Karina, Rosenberg, Andrew, Hu, Guozhi, Tinoco, Gabriel, Bodamer, Olaf, Trent, Jonathan C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.09.2015; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Anticancer properties; Antitumor agents; Apoptosis; Benzeneacetamides - pharmacology; Biology; Biomarkers; Biotechnology; Bone tumors; Brain cancer; Cancer therapies; Cell Line, Tumor; Cell migration; Chondrocytes; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrosarcoma; Chondrosarcoma - metabolism; Clinical trials; Dehydrogenases; Deoxyribonucleic acid; DNA; DNA sequencing; Enzyme Inhibitors - pharmacology; Enzymes; Epigenetics; Gene expression; Gene sequencing; Glutarates - metabolism; Hematology; Humans; Hypoxia; Imidazoles - pharmacology; Inhibitors; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - antagonists & inhibitors; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Mass spectrometry; Mass spectroscopy; Medical research; Medicine; Metabolism; Mutation; Mutation, Missense; Oncology; Patients; Tumors; Urine; Florida; United States > US
• DOI: 10.1371/journal.pone.0133813
• ISSN: 1932-6203

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.