9-Norbornyl-6-chloropurine (NCP) induces cell death through GSH depletion-associated ER stress and mitochondrial dysfunction

0463545 - ÚOCHB 2017 RIV US eng J - Článek v odborném periodiku
Plačková, Pavla - Šála, Michal - Šmídková, Markéta - Dejmek, Milan - Hřebabecký, Hubert - Nencka, Radim - Thibaut, H. J. - Neyts, J. - Mertlíková-Kaiserová, Helena
9-Norbornyl-6-chloropurine (NCP) induces cell death through GSH depletion-associated ER stress and mitochondrial dysfunction.
Free Radical Biology and Medicine. Roč. 97, Aug (2016), s. 223-235. ISSN 0891-5849. E-ISSN 1873-4596
Grant CEP: GA MŠMT LO1302; GA ČR GAP303/11/1297
Institucionální podpora: RVO:61388963
Klíčová slova: glutathione-S-transferase * oxidative stress * leukemia
Kód oboru RIV: CE - Biochemie
Impakt faktor: 5.606, rok: 2016
http://www.sciencedirect.com/science/article/pii/S0891584916302921

9-Norbornyl-6-chloropurine (NCP) is a representative of a series of antienteroviral bicycle derivatives with selective cytotoxicity towards leukemia cell lines. In this work we explored the mechanism of the antileukemic activity of NCP in T-cell lymphoblast cells (CCRF-CEM). Specifically, we searched for a potential link between its ability to induce cell death on the one hand and to modulate intracellular glutathione (GSH) that is necessary to its metabolic transformation via glutathione-S-transferase on the other hand. We have observed that GSH levels decreased rapidly in NCP-treated cells. Despite a complete regeneration following 24 h of incubation with NCP, this profound drop in cellular GSH content triggered ER stress, ROS production and lipid peroxidation leading to the loss of mitochondrial membrane potential (MMP). These events induced concentration-dependent cell cycle arrest in G2/M phase and apoptosis. Both MMP loss and apoptosis were reversed by sulfhydryl-containing compounds (GSH, Nacetyl-L-cysteine). Furthermore, we have also shown that NCP-induced GSH decrease activated the Nrf2 pathway and its downstream targets NAD(P)H:quinone oxidoreductase (NQO-1) and glutamate cysteine ligase modifier subunit (GCLm), thus explaining the fast restoration of GSH pool and ROS decrease. Importantly, we confirmed that the cell death-inducing properties of the compounds were co-dependent on their ability to diminish cellular GSH level by analyzing the relationships between the GSH-depleting potency and cytotoxicity in a series of other norbornylpurine analogs. Altogether, the results demonstrated that in CCRF-CEM cells NCP triggered apoptosis through GSH depletion-associated oxidative and ER stress and mitochondrial depolarization.
Trvalý link: http://hdl.handle.net/11104/0262713