[Frontiers in Bioscience E5, 706-719, January 1, 2013]
Thymoquinone induces apoptosis in malignant T-cells via generation of ROS
Eileen Manasse Dergarabetian1, Khaled Imad Ghattass1, Sally Boulos El-Sitt1, Rasha Mahmoud Al Mismar1, Chirine Omar El-Baba4, Wafica Sami Itani1, Nada Mohamad Melhem2, Hiba Ahmad El-Hajj3, Ali Abdul Hamid Bazarbachi3, Regine Schneider-Stock4, Hala Uthman Gali-Muhtasib1
1Department of Biology, American University of Beirut, Beirut, Lebanon, 2Medical Laboratory Sciences Program, American University of Beirut, Beirut, Lebanon, 3Internal Medicine, American University of Beirut, Lebanon, 4Experimental Tumor Pathology, Institute for Pathology, University Erlangen-Nuremberg, Germany
TABLE OF CONTENTS
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.