Epstein-Barr virus (EBV), which infects not only B cells but also T and natural killer (NK) cells, is associated with a variety of lymphoid
malignancies. Because EBV-associated T and NK cell
lymphomas are refractory and resistant to conventional
chemotherapy, there is a continuing need for new effective
therapies. EBV-encoded "latent
membrane protein 1" (LMP1) is a major oncogene that activates
nuclear factor kappa B (NF-κB),
c-Jun N-terminal kinase (JNK), and
phosphatidylinositol 3-kinase signaling pathways, thus promoting cell growth and inhibiting apoptosis. Recently, we screened a library of small-molecule inhibitors and isolated
heat shock protein 90 (Hsp90) inhibitors as candidate suppressors of LMP1 expression. In this study, we evaluated the effects of
BIIB021, a synthetic Hsp90 inhibitor, against EBV-positive and -negative T and NK
lymphoma cell lines.
BIIB021 decreased the expression of LMP1 and its downstream signaling
proteins, NF-κB, JNK, and Akt, in EBV-positive cell lines. Treatment with
BIIB021 suppressed proliferation in multiple cell lines, although there was no difference between the EBV-positive and -negative lines.
BIIB021 also induced apoptosis and arrested the cell cycle at G1 or G2. Further, it down-regulated the
protein levels of CDK1, CDK2, and
cyclin D3. Finally, we evaluated the in vivo effects of the
drug;
BIIB021 inhibited the growth of EBV-positive NK cell
lymphomas in a murine xenograft model. These results suggest that
BIIB021 has suppressive effects against T and NK
lymphoma cells through the induction of apoptosis or a cell cycle arrest. Moreover,
BIIB021 might help to suppress EBV-positive T or NK cell
lymphomas via the down-regulation of LMP1 expression.