mTOR Inhibitors Induce Cell-Cycle Arrest and Inhibit Tumor Growth in Epstein-Barr Virus-Associated T and Natural Killer Cell Lymphoma Cells

作者：Kawada Jun ichi; Ito Yoshinori^*; Iwata Seiko; Suzuki Michio; Kawano Yoshihiko; Kanazawa Tetsuhiro; Siddiquey Mohammed Nure Alam; Kimura Hiroshi

来源：Clinical Cancer Research, 2014, 20(21): 5412-5422.

DOI：10.1158/1078-0432.CCR-13-3172

Purpose: Epstein-Barr virus (EBV) infects B cells, as well as T cells and natural killer (NK) cells, and is associated with T or NK cell lymphoid malignancies. In various tumor cells, mTOR performs an essential function together with Akt with regard to cell growth. We investigated the effects of mTOR inhibitors on EBV-associated T-and NK-cell lymphomas.
Experimental Design: We investigated the Akt/mTOR activation pathway in EBV-positive and -negative T-and NK-cell lines (SNT13, SNT16, Jurkat, SNK6, KAI3, and KHYG1). We evaluated the antitumor effects of mTOR inhibitors (rapamycin and its analogue, CCI-779) against these cell lines in culture and in a murine xenograft model that was established by subcutaneous injection of SNK6 cells into NOG mice.
Results: All EBV-positive and -negative T- and NK-cell lines tested displayed activation of the Akt/mTOR pathway, and treatment with mTOR inhibitors suppressed mTOR activation. The inhibitors inducedG1 cell-cycle arrest and inhibited cell proliferation in T- and NK-cell lines. Overall, T cell lines were more sensitive to rapamycin, but there were no significant differences between EBV-positive and -negative cell lines. Treatment with rapamycin did not affect lytic or latent EBV gene expression. Intraperitoneal treatment with CCI-779 significantly inhibited the growth of established tumors in NOG mice and reduced the EBV load in peripheral blood.
Conclusion: These results suggest that inhibition of mTOR signaling is a promising new strategy for improving treatment of EBV-associated T-and NK-cell lymphoma.

• 出版日期2014-11-1