title: Diallyl trisulfide induces apoptosis by suppressing NF-κB signaling through destabilization of TRAF6 in primary effusion lymphoma.
abstract: The allyl sulfides, including diallyl sulfide (DAS), diallyl disulfide (DAD), and diallyl trisulfide (DAT), contained in garlic and members of the Allium family, have a variety of pharmacological activities. Therefore, allyl sulfides have been evaluated as potential novel chemotherapeutic agents. Here, we found that DAT inhibited nuclear factor-κB (NF-κB) signaling and induced apoptosis in primary effusion lymphoma (PEL), a subtype of non-Hodgkin's B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). We examined the cytotoxic effects of DAS, DAD and DAT on PEL cells. DAT significantly reduced the viability of PEL cells compared with uninfected B-lymphoma cells, and induced the apoptosis of PEL cells by activating caspase-9. DAT induced stabilization of IκBα, and suppressed NF-κB transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated IκBα stabilization. The results indicated that DAT stabilized IκBα by inhibiting the phosphorylation of IκBα by the IκB kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKKβ-phosphorylation through downregulation of TRAF6. It is known that activation of NF-κB is essential for survival of PEL cells. In fact, the NF-κB inhibitor BAY11-7082 induced apoptosis in PEL cells. In addition, DAT suppressed the production of progeny virus from PEL cells. The administration of DAT suppressed the development of PEL cells and ascites in SCID mice xenografted with PEL cells. These findings provide evidence that DAT has antitumor activity against PEL cells in vitro and in vivo, suggesting it to be a novel therapeutic agent for the treatment of PEL.
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Zenpei
authors.initials: Z
authors.lastname: Shigemi
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Furukawa
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Hosokawa
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Setsuya
authors.initials: S
authors.lastname: Minami
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Matsuhiro
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Shiori
authors.initials: S
authors.lastname: Nakata
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kagawa
authors.affiliation: Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kitaku, Sapporo 060-0812, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kitaku, Sapporo 060-0812, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeda
authors.affiliation: Department of Cell Biology, Kyoto Pharmaceutical University, Yamashinaku, Kyoto 607-8412, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fujimuro
mesh_terms: D000498:Allyl Compounds / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000096:biosynthesis* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D054685:Lymphoma, Primary Effusion / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009570:Nitriles / Q000008:administration & dosage; D010766:Phosphorylation; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000008:administration & dosage*; D013450:Sulfones / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000498:Allyl Compounds; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; C000606205:Nfkbia protein, mouse; D009570:Nitriles; D013440:Sulfides; D013450:Sulfones; C120635:TAX1BP1 protein, human; C042577:diallyl trisulfide; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase