title: Thymoquinone induces apoptosis in malignant T-cells via generation of ROS.
abstract: We show that HTLV-1 negative leukemia cells are more sensitive to TQ due to higher levels of drug-induced reactive oxygen species (ROS). PreG1 population in HTLV-1 negative Jurkat and CEM was higher than HTLV-1 transformed HuT-102 and MT-2 cells. Peripheral blood mononuclear cells were more resistant. Hoechst staining indicated more features of apoptosis, namely nuclear blebs and shrunken nuclei in HuT-102 than Jurkat. A greater depletion of the antioxidant enzyme glutathione occurred in Jurkat, which consequently led to an increase in ROS, loss of mitochondrial membrane potential, cytochrome c release, activation of caspases 3 and 9, and cleavage of PARP. Treatment with z-VAD-fmk partially reversed TQ-induced apoptosis, suggesting a caspase-dependent mechanism. N-acetyl cysteine prevented apoptosis providing evidence that cell death is ROS-dependent. Catalase prevented apoptosis to a lesser extent than NAC. In summary, TQ induces apoptosis in adult T cell leukemia/lymphoma by decreasing glutathione and increasing ROS, and levels of ROS underlie the differential cellular response to TQ. Our data suggest a potential therapeutic role for TQ in sensitizing HTLV-I-negative T-cell lymphomas.
authors.affiliation: Department of Biology, American University of Beirut, Beirut, Lebanon.
authors.forename: Eileen Manasse
authors.initials: EM
authors.lastname: Dergarabetian
authors.forename: Khaled Imad
authors.initials: KI
authors.lastname: Ghattass
authors.forename: Sally Boulos
authors.initials: SB
authors.lastname: El-Sitt
authors.forename: Rasha Mahmoud
authors.initials: RM
authors.lastname: Al-Mismar
authors.forename: Chirine Omar
authors.initials: CO
authors.lastname: El-Baba
authors.forename: Wafica Sami
authors.initials: WS
authors.lastname: Itani
authors.forename: Nada Mohamad
authors.initials: NM
authors.lastname: Melhem
authors.forename: Hiba Ahmad
authors.initials: HA
authors.lastname: El-Hajj
authors.forename: Ali Abdul Hamid
authors.initials: AA
authors.lastname: Bazarbachi
authors.forename: Regine
authors.initials: R
authors.lastname: Schneider-Stock
authors.forename: Hala Uthman
authors.initials: HU
authors.lastname: Gali-Muhtasib
mesh_terms: D000590:Amino Acid Chloromethyl Ketones; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D002374:Catalase; D005978:Glutathione / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000821:virology; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D016227:Benzoquinones; D017382:Reactive Oxygen Species; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D002374:Catalase; D005978:Glutathione; C003466:thymoquinone