PMID- 34934426
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20220507
IS  - 1792-1015 (Electronic)
IS  - 1792-0981 (Print)
IS  - 1792-0981 (Linking)
VI  - 23
IP  - 1
DP  - 2022 Jan
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.
PG  - 47
LID - 10.3892/etm.2021.10969 [doi]
LID - 47
AB  - Treatment of resistant or recurrent acute lymphoblastic leukemia (ALL) remains a 
      challenge. It was previously demonstrated that the adhesion molecule integrin alpha4, 
      referred to hereafter as alpha4, 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 alpha4 with natalizumab or inhibition using the small molecule antagonist TBC3486 
      sensitized relapsed ALL cells to chemotherapy. However, alpha4-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 alpha4 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 alpha4 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 alpha4-VCAM-1 interaction 
      using AVA4746 for the treatment of drug-resistant B-lineage ALL.
CI  - Copyright: (c) Ruan et al.
FAU - Ruan, Yongsheng
AU  - Ruan Y
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.
AD  - Department of Pediatrics, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong 510515, P.R. China.
FAU - Kim, Hye Na
AU  - Kim HN
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.
FAU - Ogana, Heather A
AU  - Ogana HA
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.
FAU - Gang, Eun Ji
AU  - Gang EJ
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.
FAU - Li, Shuangyue
AU  - Li S
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.
FAU - Liu, Hsiao-Chuan
AU  - Liu HC
AD  - Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Bhojwani, Deepa
AU  - Bhojwani D
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.
FAU - Wayne, Alan S
AU  - Wayne AS
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.
FAU - Yang, Mo
AU  - Yang M
AD  - Department of Pediatrics, Nanfang Hospital, Southern Medical University, 
      Guangzhou, Guangdong 510515, P.R. China.
AD  - Research Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, 
      Shenzhen, Guangdong 518107, P.R. China.
FAU - Kim, Yong-Mi
AU  - Kim YM
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.
LA  - eng
GR  - R01 CA172896/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20211115
PL  - Greece
TA  - Exp Ther Med
JT  - Experimental and therapeutic medicine
JID - 101531947
PMC - PMC8652384
OTO - NOTNLM
OT  - acute lymphoblastic leukemia
OT  - angiogenesis
OT  - cell adhesion-mediated drug resistance
OT  - integrin alpha4
OT  - vascular cell adhesion molecule-1
COIS- The authors declare that they have no competing interests.
EDAT- 2021/12/23 06:00
MHDA- 2021/12/23 06:01
PMCR- 2021/11/15
CRDT- 2021/12/22 06:48
PHST- 2021/01/26 00:00 [received]
PHST- 2021/09/14 00:00 [accepted]
PHST- 2021/12/22 06:48 [entrez]
PHST- 2021/12/23 06:00 [pubmed]
PHST- 2021/12/23 06:01 [medline]
PHST- 2021/11/15 00:00 [pmc-release]
AID - ETM-23-1-10969 [pii]
AID - 10.3892/etm.2021.10969 [doi]
PST - ppublish
SO  - Exp Ther Med. 2022 Jan;23(1):47. doi: 10.3892/etm.2021.10969. Epub 2021 Nov 15.