Ruan Yongsheng, Kim Hye Na, Ogana Heather A, Gang Eun Ji, Li Shuangyue, Liu Hsiao-Chuan, Bhojwani Deepa, Wayne Alan S, Yang Mo, Kim Yong-Mi
Department of Pediatrics, Division of Hematology-Oncology, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
Exp Ther Med. 2022 Jan;23(1):47. doi: 10.3892/etm.2021.10969. Epub 2021 Nov 15.
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 co-culture = model of primary B-ALL cells and an 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, 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 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 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.
难治性或复发性急性淋巴细胞白血病(ALL)的治疗仍然是一项挑战。先前的研究表明,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TBC3486抑制可使复发的ALL细胞对化疗敏感。然而,迄今为止,α4靶向治疗在临床上尚未用于白血病的治疗。在本研究中,探索了使用新型非肽小分子整合素α4拮抗剂AVA4746作为对抗耐药性B-ALL的潜在新方法。利用原代B-ALL细胞的共培养模型和患者来源的B-ALL细胞的异种移植模型来评估AVA4746。进行了VLA-4构象激活、细胞粘附/去粘附、内皮管形成、白血病细胞动员和存活分析。AVA4746对B-ALL细胞具有高亲和力,在该细胞中它还能有效阻断配体与VCAM-1的结合。此外,AVA4746导致原代B-ALL细胞与VCAM-1发生功能性去粘附。使用AVA4746抑制α4也可防止血管生成,并且当与由长春新碱、地塞米松和L-天冬酰胺酶组成的化疗联合应用时,它可延长B-ALL异种移植模型中约33%小鼠的生存期。这些数据表明,使用AVA4746靶向α4-VCAM-1相互作用治疗耐药性B系ALL具有潜力。