title: γ-Tocotrienol induces apoptosis in human T cell lymphoma through activation of both intrinsic and extrinsic pathways.
abstract: Tocotrienols are members of vitamin E family and possess broad biological activities including antioxidant, anti-inflammatory and antitumor effects. In the present study, we examine the potential of α-tocotrienol (AT) and γ-tocotrienol (GT) in inhibiting the proliferation of human T cell lymphoma Jurkat cells and elucidate the pathways involved in anti tumor effects of GT. GT but not AT inhibited proliferation and induced apoptosis in Jurkat cells in a dose dependent manner. GT treatment resulted in elevated mitochondrial ROS production, activation of JNK and suppression of ERK and p38 MAPK. GT also induced calcium release, loss of mitochondrial membrane potential and cytochrome c release from the mitochondria. These changes were accompanied by increase in Bax expression with a concomitant decrease in Bcl-xl expression suggesting activation of mitochondrial apoptotic pathway. GT induced increase in mitochondrial ROS was abrogated by catalase. Besides, GT also up-regulated surface expression of Fas and FasL on Jurkat cells. Further, caspase activation and PARP degradation were also seen in cells treated with GT. Inhibitors of caspase-8 and caspase-9 significantly abrogated GT mediated apoptosis. In contrast GT was not toxic to normal human peripheral blood mononuclear cells suggesting differential cytotoxicity towards normal lymphocytes and transformed lymphoma cells. Cellular uptake studies with tocotrienols showed higher intracellular accumulation of GT as compared to AT which may be responsible for its better antitumor activity. Our results show antitumor effects of GT in human lymphoma cells via increased mitochondrial ROS generation and activation of both intrinsic and extrinsic apoptotic pathways.
authors.affiliation: Radiation Biology & Health Sciences Division, Bhabha Atomic Research Centre, Mumbai, India.
authors.forename: Chandan
authors.initials: C
authors.lastname: Wilankar
authors.forename: Nazir M
authors.initials: NM
authors.lastname: Khan
authors.forename: Rahul
authors.initials: R
authors.lastname: Checker
authors.forename: Deepak
authors.initials: D
authors.lastname: Sharma
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Patwardhan
authors.forename: Vikram
authors.initials: V
authors.lastname: Gota
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Sandur
authors.forename: T P A
authors.initials: TP
authors.lastname: Devasagayam
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002839:Chromans; D016207:Cytokines; D053222:Fas Ligand Protein; D017382:Reactive Oxygen Species; D019014:fas Receptor; D014810:Vitamin E; C013649:plastochromanol 8; D020169:Caspases; D002118:Calcium