Diallyl trisulfide induces apoptosis by suppressing NF-kappa B signaling through destabilization of TRAF6 in primary effusion lymphoma

作者：Shigemi Zenpei; Furukawa Yoshiki; Hosokawa Kohei; Minami Setsuya; Matsuhiro Jumpei; Nakata Shiori; Watanabe Tadashi; Kagawa Hiroki; Nakagawa Koji; Takeda Hiroshi; Fujimuro Masahiro^*

来源：International Journal of Oncology, 2016, 48(1): 293-304.

DOI：10.3892/ijo.2015.3247

• Kaposi's sarcoma-associated herpesvirus
• proteasome
• primary effusion lymphoma
• nuclear factor-kappa B
• TRAF6
• ubiquitination

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-kappa B (NF-kappa B) 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 I kappa B alpha, and suppressed NF-kappa B transcriptional activity in PEL cells. We examined the mechanism underlying DAT-mediated I kappa B alpha stabilization. The results indicated that DAT stabilized I kappa B alpha by inhibiting the phosphorylation of I kappa B alpha by the I kappa B kinase (IKK) complex. Furthermore, DAT induced proteasomal degradation of TRAF6, and DAT suppressed IKK beta-phosphorylation through downregulation of TRAF6. It is known that activation of NF-kappa B is essential for survival of PEL cells. In fact, the NF-kappa B 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.

• 出版日期2016-1