TY - JOUR
AB - 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.
AD - 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 Radiology, Mayo Clinic, Rochester, MN 55905, USA
Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
AU - Ruan,Yongsheng
AU - Kim,Hye,Na
AU - Ogana,Heather,A.
AU - Gang,Eun,Ji
AU - Li,Shuangyue
AU - Liu,Hsiao-Chuan
AU - Bhojwani,Deepa
AU - Wayne,Alan,S.
AU - Yang,Mo
AU - Kim,Yong-Mi
DA - 2022/01/01
DO - 10.3892/etm.2021.10969
IS - 1
JO - Exp Ther Med
KW - integrin α4
vascular cell adhesion molecule‑1
angiogenesis
cell adhesion‑mediated drug resistance
acute lymphoblastic leukemia
PY - 2022
SN - 1792-0981
1792-1015
SP - 47
ST - 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
T2 - Experimental and Therapeutic Medicine
TI - 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
UR - https://doi.org/10.3892/etm.2021.10969
VL - 23
ER -