title: Bortezomib induces apoptosis in T lymphoma cells and natural killer lymphoma cells independent of Epstein-Barr virus infection.
abstract: Epstein-Barr virus (EBV), which infects not only B cells, but also T cells and natural killer (NK) cells, is associated with multiple lymphoid malignancies. Recently, the proteasome inhibitor bortezomib was reported to induce apoptosis of EBV-transformed B cells. We evaluated the killing effect of this proteasome inhibitor on EBV-associated T lymphoma cells and NK lymphoma cells. First, we found that bortezomib treatment decreased the viability of multiple T and NK cell lines. No significant difference was observed between EBV-positive and EBV-negative cell lines. The decreased viability in response to bortezomib treatment was abrogated by a pan-caspase inhibitor. The induction of apoptosis was confirmed by flow cytometric assessment of annexin V staining. Additionally, cleavage of caspases and polyadenosine diphosphate-ribose polymerase, increased expression of phosphorylated IκB, and decreased expression of inhibitor of apoptotic proteins were detected by immunoblotting in bortezomib-treated cell lines. We found that bortezomib induced lytic infection in EBV-positive T cell lines, although the existence of EBV did not modulate the killing effect of bortezomib. Finally, we administered bortezomib to peripheral blood mononuclear cells from five patients with EBV-associated lymphoproliferative diseases. Bortezomib had a greater killing effect on EBV-infected cells. These results indicate that bortezomib killed T or NK lymphoma cells by inducing apoptosis, regardless of the presence or absence of EBV.
authors.affiliation: Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Iwata
authors.forename: Shoko
authors.initials: S
authors.lastname: Yano
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Ito
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ushijima
authors.forename: Kensei
authors.initials: K
authors.lastname: Gotoh
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kawada
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Isobe
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D004789:Enzyme Activation / Q000187:drug effects; D020031:Epstein-Barr Virus Infections / Q000150:complications* / Q000821:virology; D005260:Female; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008223:Lymphoma / Q000821:virology*; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000821:virology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology / Q000821:virology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib