TY - JOUR
T1 - Inhibition of mutant IDH1 decreases D-2-HG levels without affecting tumorigenic properties of chondrosarcoma cell lines
AU - Suijker, Johnny
AU - Oosting, Jan
AU - Koornneef, Annemarie
AU - Struys, Eduard A.
AU - Salomons, Gajja S.
AU - Schaap, Frank G.
AU - Waaijer, Cathelijn J.F.
AU - Wijers-Koster, Pauline M.
AU - Briaire-de Bruijn, Inge H.
AU - Haazen, Lizette
AU - Riester, Scott M.
AU - Dudakovic, Amel
AU - Danen, Erik
AU - Cleton-Jansen, Anne Marie
AU - van Wijnen, Andre J.
AU - Bovée, Judith V.M.G.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - AGI-5198
KW - Chondrosarcoma
KW - D-2-hydroxyglutarate
KW - Isocitrate dehydrogenase
KW - Sarcoma
UR - http://www.scopus.com/inward/record.url?scp=84930023859&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84930023859&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3723
DO - 10.18632/oncotarget.3723
M3 - Article
C2 - 25895133
AN - SCOPUS:84930023859
SN - 1949-2553
VL - 6
SP - 12505
EP - 12519
JO - Oncotarget
JF - Oncotarget
IS - 14
ER -