Diethyldithiocarbamate induces apoptosis in HHV-8-infected primary effusion             lymphoma cells via inhibition of the NF-κB pathway.
Primary effusion lymphoma (PEL) is a subtype of B-cell lymphoma caused by             human herpes virus 8/Kaposi sarcoma-associated herpes virus (HHV-8/KSHV), which             is mostly found in patients with AIDS and has poor prognosis. Nuclear factor (NF)-κB             pathway is constitutively activated in HHV-8-infected PEL cells and plays a crucial             role in tumorigenesis. Recently, it has been shown that diethyldithiocarbamate             (DDTC), an active metabolite of disulfiram, has apoptotic activity in cancer cells.             Here, we investigated the effect of DDTC on PEL using a PEL mouse model generated             by intraperitoneal injection of BC-3 cells, a PEL cell line. DDTC ameliorated             the symptoms of PEL in these mice, such as development of ascites, splenomegaly             and increase of body weight, in comparison with PBS-treated controls. Moreover,             we determined in vitro that DDTC suppressed the constitutively activated NF-κB             pathway in BC-3 cells. Methylthiotetrazole assay revealed that the cell proliferation             of various PEL cell lines was significantly suppressed by the treatment of DDTC.             DDTC also induced the expression of cleaved caspase-3, an apoptosis marker, whereas             the addition of Q-VD-OPh, a pan-caspase inhibitor, inhibited cell apoptosis induced             by DDTC treatment. Together, our results indicated that DDTC induces apoptosis             via inhibition of the NF-κB signaling pathway in HHV-8-infected PEL cells. This             study suggests the potential use of DDTC as a therapeutic approach for PEL.
Department of Molecular Medicine, Graduate School of Pharmaceutical                     Sciences, Global COE 'Cell Fate Regulation Research and Education Unit',                     Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan.
Takashi
T
Matsuno
Ryusho
R
Kariya
Shuichiro
S
Yano
Saori
S
Morino-Koga
Manabu
M
Taura
Mary Ann
MA
Suico
Yuichiro
Y
Shimauchi
Shingo
S
Matsuyama
Yuka
Y
Okamoto
Tsuyoshi
T
Shuto
Hirofumi
H
Kai
Seiji
S
Okada
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004050:Ditiocarb / Q000494:pharmacology*; D005260:Female; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000473:pathology / Q000821:virology; D019288:Herpesvirus 8, Human / Q000502:physiology*; D006801:Humans; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
D016328:NF-kappa B; D004050:Ditiocarb; D053148:Caspase 3