The potential efficacy and mechanism of bendamustine in entra-nodal NK/T cell lymphoma.

Bendamustine has been shown to have anti-tumor activities in hematological malignancies, but the role of bendamustine in natural killer (NK)/T cell lymphoma (NKTCL) treatment is unclear. Our study has shown that bendamustine had potent growth-inhibitory and apoptosis-inducing effects on NKTCL cells. Interestingly, we noticed that the combination of either gemcitabine or etoposide results in additive or synergistic cytotoxicity. Bendamustine induced mitochondria-mediated apoptosis in concentration- and time-dependent manners in NKTCL cells, shown as down-regulation of Bcl-2 and activation of cleavage of caspases 3, 7, 9 and poly adenosinediphosphate-ribose polymerase (PARP). Bendamustine arrested NKTCL cells in G2/M phase, with downregulation of expression of cyclin B1 and upregulation of expression of p-cdc2, p-cdc25c and p-P53. Furthermore, we confirmed that bendamustine activated DNA damage response (DDR) directly or through Ataxia Telangiectasia Mutated Protein (ATM)/Chk2 and ATR/Chk1 pathway and increased the intracellular reactive oxygen species (ROS) level in NKTCL cells, which caused G2/M phase arrest and apoptosis. Bendamustine also inhibited phosphorylation of transcriptional factor STAT3, contributing to cell apoptosis and proliferation inhibition. Finally, we verified the effect of bendamustine on NKTCL cells in vivo. It showed that bendamustine dramatically inhibited the growth of the subcutaneous tumor, with no obvious impact on mice weight. These findings demonstrate that bendamustine activates DDR pathway, induces the accumulation of intracellularROS level as well as inhibition of STAT3, leading to cell apoptosis and G2/M cell cycle arrest in NKTCL cells, which indicates that bendamustine dramatically suppressed NKTCL both in vitro and in vivo and provides a potential therapeutic strategy in the treatment of NK/T lymphoma.