The potential efficacy and mechanism of bendamustine in entra‐nodal NK/T cell lymphoma
The potential efficacy and mechanism of bendamustine in entra‐nodal NK/T cell lymphoma
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DOI：
10.1002/hon.3007
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发表时间：
2022-04
影响因子：
3.3
通讯作者：
Yuyang Gao;Xiao-yan Feng;Wenting Song;Hongwen Li;C. Shi;M. Jin;Zhaoming Li;Lei Zhang;Mingzhi Zhang
中科院分区：
文献类型：
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作者：
Yuyang Gao;Xiao-yan Feng;Wenting Song;Hongwen Li;C. Shi;M. Jin;Zhaoming Li;Lei Zhang;Mingzhi Zhang
苯达莫司汀已被证明在血液系统恶性肿瘤中具有抗肿瘤活性，但其在自然杀伤(NK)/T细胞淋巴瘤(NKTCL)治疗中的作用尚不清楚。我们的研究表明苯达莫司汀对NKTCL细胞具有明显的生长抑制和诱导凋亡作用。有趣的是，我们注意到吉西他滨或依托泊苷的组合会导致相加或协同的细胞毒性。苯达莫司汀以浓度和时间依赖的方式诱导NKTCL细胞线粒体介导的细胞凋亡，表现为Bcl2表达下调，caspase3、7、9和多聚腺苷二磷酸核糖聚合酶(PARP)的裂解激活。苯达莫司汀将NKTCL细胞阻滞于G2/M期，下调细胞周期蛋白B1的表达，上调p-cdc2、p-cdc25c和p-p53的表达。此外，我们还证实苯达莫司汀直接或通过共济失调毛细血管扩张突变蛋白(ATM)/Chk2和ATR/Chk1途径激活DNA损伤反应(DDR)，并增加NKTCL细胞内活性氧(ROS)水平，导致G2/M期停滞和细胞凋亡。苯达莫司汀还抑制转录因子STAT3的磷酸化，促进细胞凋亡和抑制增殖。最后，我们在体内验证了苯达莫司汀对NKTCL细胞的作用。结果表明，苯达莫司汀显著抑制皮下肿瘤的生长，对小鼠体重无明显影响。这些结果表明，苯达莫司汀激活DDR通路，诱导细胞内ROS水平积聚，抑制STAT3，导致NKTCL细胞凋亡和G2/M期停滞，这表明苯达莫司汀在体内外均显著抑制NKTCL，为治疗NK/T淋巴瘤提供了一种潜在的治疗策略。
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.