IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity

Mohammed Khurshed; Niels Aarnoudse; Renske Hulsbos; Vashendriya V V Hira; Hanneke W M van Laarhoven; Johanna W Wilmink; Remco J Molenaar; Cornelis J F van Noorden

doi:10.1096/fj.201800547R

IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity

FASEB J. 2018 Jun 7;32(11):fj201800547R. doi: 10.1096/fj.201800547R. Online ahead of print.

Authors

Mohammed Khurshed^{1

2}, Niels Aarnoudse¹, Renske Hulsbos¹, Vashendriya V V Hira¹, Hanneke W M van Laarhoven^{1

2}, Johanna W Wilmink^{1

2}, Remco J Molenaar^{1

2}, Cornelis J F van Noorden^{1

3}

Affiliations

¹ Department of Medical Biology, Cancer Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
² Department of Medical Oncology, Cancer Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and.
³ Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Ljubljana, Slovenia.

Abstract

Isocitrate dehydrogenase ( IDH1)-1 is mutated in various types of human cancer, and the presence of this mutation is associated with improved responses to irradiation and chemotherapy in solid tumor cells. Mutated IDH1 (IDH1^MUT) enzymes consume NADPH to produce d-2-hydroxyglutarate (d-2HG) resulting in the decreased reducing power needed for detoxification of reactive oxygen species (ROS), for example. The objective of the current study was to investigate the mechanism behind the chemosensitivity of the widely used anticancer agent cisplatin in IDH1^MUT cancer cells. Oxidative stress, DNA damage, and mitochondrial dysfunction caused by cisplatin treatment were monitored in IDH1^MUT HCT116 colorectal cancer cells and U251 glioma cells. We found that exposure to cisplatin induced higher levels of ROS, DNA double-strand breaks (DSBs), and cell death in IDH1^MUT cancer cells, as compared with IDH1 wild-type ( IDH1^WT) cells. Mechanistic investigations revealed that cisplatin treatment dose dependently reduced oxidative respiration in IDH1^MUT cells, which was accompanied by disturbed mitochondrial proteostasis, indicative of impaired mitochondrial activity. These effects were abolished by the IDH1^MUT inhibitor AGI-5198 and were restored by treatment with d-2HG. Thus, our study shows that altered oxidative stress responses and a vulnerable oxidative metabolism underlie the sensitivity of IDH1^MUT cancer cells to cisplatin.-Khurshed, M., Aarnoudse, N., Hulsbos, R., Hira, V. V. V., van Laarhoven, H. W. M., Wilmink, J. W., Molenaar, R. J., van Noorden, C. J. F. IDH1-mutant cancer cells are sensitive to cisplatin and an IDH1-mutant inhibitor counteracts this sensitivity.

Keywords: 2-hydroxyglutarate; chemosensitivity; cis-diamminedichloroplatinum; isocitrate dehydrogenase.