Induction of apoptosis in Epstein-Barr virus-infected B-lymphocytes by the NF-kappaB inhibitor DHMEQ.
Epstein-Barr virus (EBV) causes EBV-associated lymphoproliferative diseases in patients with profound immune suppression. Most of these diseases are life-threatening and the prognosis of AIDS-associated lymphomas is extremely unfavorable. Polyclonal expansion of virus infected B-cell predisposes them to transformation. We investigated the possibility of nuclear factor kappa B (NF-kappaB) inhibition by dehydroxymethylepoxyquinomicin (DHMEQ) for the treatment and prevention of EBV-associated lymphoproliferative diseases. We examined the effect of DHMEQ on apoptosis induction in four EBV-transformed lymphoblastoid cell lines as well as peripheral blood mononuclear cells infected with EBV under immunosuppressed condition. DHMEQ inhibits NF-kappaB activation in EBV-transformed lymphoblastoid cell lines and induces apoptosis by activation of mitochondrial and membranous pathways. Using an in vivo NOD/SCIDgammac mouse model, we showed that DHMEQ has a potent inhibitory effect on the growth of lymphoblastoid cells. In addition, DHMEQ selectively purges EBV-infected cells expressing latent membrane protein (LMP) 1 from peripheral blood mononuclear cells and inhibits the outgrowth of lymphoblastoid cells. These results suggest that NF-kappaB is a molecular target for the treatment and prevention of EBV-associated lymphoproliferative diseases. As a potent NF-kappaB inhibitor, DHMEQ is a potential compound for applying this strategy in clinical medicine.
Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan.
Ariko
A
Miyake
Md Zahidunnabi
MZ
Dewan
Takaomi
T
Ishida
Mariko
M
Watanabe
Mitsuo
M
Honda
Tetsutaro
T
Sata
Naoki
N
Yamamoto
Kazuo
K
Umezawa
Toshiki
T
Watanabe
Ryouichi
R
Horie
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000821:virology*; D001549:Benzamides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D003512:Cyclohexanones / Q000494:pharmacology*; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D008232:Lymphoproliferative Disorders / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D007155:Immunologic Factors; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin