Therapeutic Interaction of Apatinib and Chidamide in T-Cell Acute Lymphoblastic Leukemia through Interference with Mitochondria Associated Biogenesis and Intrinsic Apoptosis.
Therapeutic Interaction of Apatinib and Chidamide in T-Cell Acute Lymphoblastic Leukemia through Interference with Mitochondria Associated Biogenesis and Intrinsic Apoptosis.
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阿帕替尼和西达本胺通过干扰线粒体相关生物发生和内在细胞凋亡在 T 细胞急性淋巴细胞白血病中的治疗相互作用
DOI：
10.3390/jpm11100977
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发表时间：
2021-09-29
影响因子：
--
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Zhong M;Lin F;Jiang Y;Pan G;Tan J;Zhou H;Lai Q;Chen Q;Deng M;Zha J;Xu B
T细胞急性淋巴细胞白血病（T-ALL）的临床结局较差，治疗选择有限，这表明迫切需要新的治疗方法。我们之前的研究表明，阿帕替尼，一种口服选择性VEGFR-2拮抗剂，在T-ALL中非常有效。此外，西达米特，一种组蛋白脱乙酰酶抑制剂，已被证明在临床前和临床环境中对T-ALL具有细胞毒性。然而，阿帕替尼和西达米特在T-ALL中的治疗相互作用是否仍然未知。在这项研究中，阿帕替尼和西达米胺在体外降低T-ALL的细胞活力并诱导细胞凋亡。值得注意的是，与阿帕替尼或西达米胺单药相比，联合方案在消除T-ALL患者来源的异种移植物（PDX）模型的脾脏和骨髓中的白血病负荷方面更有效。从机制上讲，阿帕替尼和西达胺的相加抗白血病作用与线粒体呼吸抑制以及参与柠檬酸循环和氧化磷酸化（OXPHOS）的几种限速酶丰度水平下调有关。此外，阿帕替尼通过激活线粒体介导的细胞凋亡途径和阻碍线粒体生物发生来增强西达明对T-ALL的抗白血病作用。总之，该研究提供了阿帕替尼联合西达米胺在T-ALL治疗中的潜在作用，并保证了该联合治疗在T-ALL患者中的进一步临床评价。
T-cell acute lymphoblastic leukemia (T-ALL) shows poor clinical outcome and has limited therapeutic options, indicating that new treatment approaches for this disease are urgently required. Our previous study demonstrated that apatinib, an orally selective VEGFR-2 antagonist, is highly effective in T-ALL. Additionally, chidamide, a histone deacetylase inhibitor, has proven to be cytotoxic against T-ALL in preclinical and clinical settings. However, whether the therapeutic interaction of apatinib and chidamide in T-ALL remains unknown. In this study, apatinib and chidamide acted additively to decrease cell viability and induce apoptosis in T-ALL in vitro. Notably, compared with apatinib or chidamide alone, the combinational regimen was more efficient in abrogating the leukemia burden in the spleen and bone marrow of T-ALL patient-derived xenograft (PDX) models. Mechanistically, the additive antileukemia effect of apatinib and chidamide was associated with suppression of mitochondrial respiration and downregulation of the abundance levels of several rate-limiting enzymes that are involved in the citric acid cycle and oxidative phosphorylation (OXPHOS). In addition, apatinib enhanced the antileukemia effect of chidamide on T-ALL via activation of the mitochondria-mediated apoptosis pathway and impediment of mitochondrial biogenesis. Taken together, the study provides a potential role for apatinib in combination with chidamide in the management of T-ALL and warrants further clinical evaluations of this combination in patients with T-ALL.
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影响因子：
5.7
作者：
Markovic, Ana;MacKenzie, Karen L.;Lock, Richard B.
通讯作者：
Lock, Richard B.
影响因子：
20.3
作者：
Aguayo, A;Kantarjian, H;Albitar, M
通讯作者：
Albitar, M
影响因子：
21.3
作者：
Boroughs LK;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
伏立诺他和奎纳克林通过增加活性氧和抑制线粒体自噬对 T 细胞急性淋巴细胞白血病具有协同作用。
影响因子：
9
作者：
Jing B;Jin J;Xiang R;Liu M;Yang L;Tong Y;Xiao X;Lei H;Liu W;Xu H;Deng J;Zhou L;Wu Y
通讯作者：
Wu Y
西达本胺联合化疗治疗难治性和复发性T淋巴细胞淋巴瘤/白血病
影响因子：
2.6
作者：
Guan, Wei;Jing, Yu;Yu, Li
通讯作者：
Yu, Li