In vitro and in vivo effects of AVA4746, a novel competitive antagonist of the ligand binding of VLA-4, in B-cell acute lymphoblastic leukemia.
In vitro and in vivo effects of AVA4746, a novel competitive antagonist of the ligand binding of VLA-4, in B-cell acute lymphoblastic leukemia.
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DOI：
10.3892/etm.2021.10969
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发表时间：
2022-01
影响因子：
2.7
通讯作者：
Kim YM
中科院分区：
文献类型：
--
作者：
Ruan Y;Kim HN;Ogana HA;Gang EJ;Li S;Liu HC;Bhojwani D;Wayne AS;Yang M;Kim YM
耐药或复发性急性淋巴细胞白血病（ALL）的治疗仍然是一个挑战。先前已证实粘附分子整合素α4（以下简称α4）通过与骨髓基质上的血管细胞粘附分子-1（VCAM-1）结合，介导B细胞ALL的细胞粘附介导的耐药性（CAM-DR）。此外，先前观察到用那他珠单抗阻断α4或使用小分子拮抗剂TBC 3486抑制使复发ALL细胞对化疗敏感。然而，迄今为止，α4靶向治疗在临床上不可用于治疗白血病。在本研究中，使用一种新的非肽类小分子整合素α4拮抗剂，AVA 4746，作为一个潜在的新的方法来对抗耐药的B-ALL进行了探索。使用原代B-ALL细胞的体外共培养模型和患者来源B-ALL细胞的体内异种移植模型来评价AVA 4746。进行VLA-4构象活化、细胞粘附/去粘附、内皮管形成、体内白血病细胞动员和存活测定。AVA 4746表现出与B-ALL细胞结合的高亲和力，在B-ALL细胞中，它还有效地阻断配体与VCAM-1的结合。此外，AVA 4746导致原代B-ALL细胞与VCAM-1的功能性去粘附。使用AVA 4746抑制α4也可在体外阻止血管生成，当与由阿贝新汀、地塞米松和L-天冬酰胺酶组成的化疗联合使用时，它可延长体内B-ALL异种移植模型中约33%小鼠的存活时间。这些数据表明，使用AVA 4746靶向α4-VCAM-1相互作用治疗耐药B系ALL的潜力。
Treatment of resistant or recurrent acute lymphoblastic leukemia (ALL) remains a challenge. It was previously demonstrated that the adhesion molecule integrin α4, referred to hereafter as α4, mediates the cell adhesion-mediated drug resistance (CAM-DR) of B-cell ALL by binding to vascular cell adhesion molecule-1 (VCAM-1) on bone marrow stroma. In addition, it was previously observed that the blockade of α4 with natalizumab or inhibition using the small molecule antagonist TBC3486 sensitized relapsed ALL cells to chemotherapy. However, α4-targeted therapy is not clinically available for the treatment of leukemia to date. In the present study, the use of a novel non-peptidic small molecule integrin α4 antagonist, AVA4746, as a potential new approach to combat drug-resistant B-ALL was explored. An in vitro co-culture = model of primary B-ALL cells and an in vivo xenograft model of patient-derived B-ALL cells were utilized for evaluation of AVA4746. VLA-4 conformation activation, cell adhesion/de-adhesion, endothelial tube formation, in vivo leukemia cell mobilization and survival assays were performed. AVA4746 exhibited high affinity for binding to B-ALL cells, where it also efficiently blocked ligand-binding to VCAM-1. In addition, AVA4746 caused the functional de-adhesion of primary B-ALL cells from VCAM-1. Inhibition of α4 using AVA4746 also prevented angiogenesis in vitro and when applied in combination with chemotherapy consisting of Vincristine, Dexamethasone and L-asparaginase, it prolonged the survival of ~33% of the mice in an in vivo xenograft model of B-ALL. These data implicate the potential of targeting the α4-VCAM-1 interaction using AVA4746 for the treatment of drug-resistant B-lineage ALL.
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