Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
Autophagy Inhibition Potentiates the Anticancer Effects of a Bendamustine Derivative NL-101 in Acute T Lymphocytic Leukemia
复制标题
自噬抑制增强苯达莫司汀衍生物 NL-101 在急性 T 淋巴细胞白血病中的抗癌作用
DOI：
10.1155/2020/1520651
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发表时间：
2020-02-14
影响因子：
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通讯作者：
Zhao, Huajun
中科院分区：
文献类型：
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作者：
Gao, Hang;Lou, Siyue;Zhao, Huajun
急性T淋巴细胞白血病（T-ALL）是由T细胞祖细胞恶性转化引起的侵袭性血液病。耐药和复发是T-ALL治疗的主要困难。在这里，我们报告了NL-101的抗肿瘤效力，NL-101是一种将苯达莫司汀的氮芥基团与伏立诺他的异羟肟酸基团相结合的化合物。我们发现NL-101在T-ALL细胞系中表现出有效的抗增殖活性（IC 50 1.59-1.89 μM），伴随细胞周期阻滞和凋亡，表现为Cyclin E1、CDK 2和CDK 4蛋白表达增加以及PARP裂解。此外，这种苯达莫司汀衍生的药物显示出HDACi效应（如通过组蛋白超乙酰化和p21转录所证明的）和DNA损伤效应（如通过γ-H2 AX的增加所证明的）。有趣的是，我们发现NL-101通过抑制Akt-mTOR信号传导途径诱导T-ALL细胞中的自噬，如LC 3-I向LC 3-II转化的增加和p62的减少所示。此外，3-甲基腺嘌呤对自噬的抑制增加了NL-101引起的凋亡细胞死亡，表明自噬具有促生存作用。总之，我们的发现为研究NL-101作为DNA/HDAC双靶向药物治疗T-ALL提供了理论基础，无论是作为单一药物还是与自噬抑制剂联合使用。
Acute T lymphocytic leukemia (T-ALL) is an aggressive hematologic resulting from the malignant transformation of T-cell progenitors. Drug resistance and relapse are major difficulties in the treatment of T-ALL. Here, we report the antitumor potency of NL-101, a compound that combines the nitrogen mustard group of bendamustine with the hydroxamic acid group of vorinostat. We found NL-101 exhibited efficient antiproliferative activity in T-ALL cell lines (IC50 1.59–1.89 μM), accompanied by cell cycle arrest and apoptosis, as evidenced by the increased expression of Cyclin E1, CDK2, and CDK4 proteins and cleavage of PARP. In addition, this bendamustine-derived drug showed both a HDACi effect as demonstrated by histone hyperacetylation and p21 transcription and a DNA-damaging effect as shown by an increase in γ-H2AX. Intriguingly, we found that NL-101-induced autophagy in T-ALL cells through inhibiting Akt-mTOR signaling pathway, as indicated by an increase in LC3-I to LC3-II conversion and decrease of p62. Furthermore, inhibition of autophagy by 3-methyladenine increased apoptotic cell death by NL-101, suggesting a prosurvival role of autophagy. In summary, our finding provides rationale for investigation of NL-101 as a DNA/HDAC dual targeting drug in T-ALL, either as a single agent or in combination with autophagy inhibitors.