title: Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines.
abstract: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a subset of benign and malignant cartilage tumors, gliomas and leukaemias. The mutant enzyme causes the production of D-2-hydroxyglutarate (D-2-HG), affecting CpG island and histone methylation. While mutations in IDH1/2 are early events in benign cartilage tumors, we evaluated whether these mutations play a role in malignant chondrosarcomas. Compared to IDH1/2 wildtype cell lines, chondrosarcoma cell lines harboring an endogenous IDH1 (n=3) or IDH2 mutation (n=2) showed up to a 100-fold increase in intracellular and extracellular D-2-HG levels. Specific inhibition of mutant IDH1 using AGI-5198 decreased levels of D-2-HG in a dose dependent manner. After 72 hours of treatment one out of three mutant IDH1 cell lines showed a moderate decrease in viability , while D-2-HG levels decreased >90%. Likewise, prolonged treatment (up to 20 passages) did not affect proliferation and migration. Furthermore, global gene expression, CpG island methylation as well as histone H3K4, -9, and -27 trimethylation levels remained unchanged. Thus, while IDH1/2 mutations cause enchondroma, malignant progression towards central chondrosarcoma renders chondrosarcoma growth independent of these mutations. Thus, monotherapy based on inhibition of mutant IDH1 appears insufficient for treatment of inoperable or metastasized chondrosarcoma patients.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Johnny
authors.initials: J
authors.lastname: Suijker
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Oosting
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Koornneef
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.affiliation: Metabolic Unit, Department of Clinical Chemistry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gajja S
authors.initials: GS
authors.lastname: Salomons
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Schaap
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Cathelijn J F
authors.initials: CJ
authors.lastname: Waaijer
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Pauline M
authors.initials: PM
authors.lastname: Wijers-Koster
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Inge H
authors.initials: IH
authors.lastname: Briaire-de Bruijn
authors.affiliation: Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Lizette
authors.initials: L
authors.lastname: Haazen
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, NY, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Riester
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, NY, USA.
authors.forename: Amel
authors.initials: A
authors.lastname: Dudakovic
authors.affiliation: Division of Toxicology, Leiden Academic Center for Drug Research, Leiden University, Leiden, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Danen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cleton-Jansen
authors.affiliation: Department of Orthopedic Surgery, Mayo Clinic, Rochester, NY, USA.
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van Wijnen
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Judith V M G
authors.initials: JV
authors.lastname: Bovée
mesh_terms: D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002853:Chromatography, Liquid; D004252:DNA Mutational Analysis; D005977:Glutarates / Q000378:metabolism*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D005977:Glutarates; C019417:alpha-hydroxyglutarate; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: AGI-5198; chondrosarcoma; d-2-hydroxyglutarate; isocitrate dehydrogenase; sarcoma