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

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