TY - JOUR
T1 - The BACH1 inhibitor ASP8731 inhibits inflammation and vaso-occlusion and induces fetal hemoglobin in sickle cell disease
AU - Belcher, John D.
AU - Nataraja, Selvaraj
AU - Abdulla, Fuad
AU - Zhang, Ping
AU - Chen, Chunsheng
AU - Nguyen, Julia
AU - Ruan, Conglin
AU - Singh, Maneet
AU - Demes, Shilpa
AU - Olson, Lyndsay
AU - Stickens, Domi
AU - Stanwix, Jeff
AU - Clarke, Emer
AU - Huang, Yongzhao
AU - Biddle, Margaret
AU - Vercellotti, Gregory M.
N1 - Publisher Copyright:
Copyright © 2023 Belcher, Nataraja, Abdulla, Zhang, Chen, Nguyen, Ruan, Singh, Demes, Olson, Stickens, Stanwix, Clark, Huang, Biddle and Vercellotti.
PY - 2023
Y1 - 2023
N2 - In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD.
AB - In sickle cell disease (SCD), heme released during intravascular hemolysis promotes oxidative stress, inflammation, and vaso-occlusion. Conversely, free heme can also activate expression of antioxidant and globin genes. Heme binds to the transcription factor BACH1, which represses NRF2-mediated gene transcription. ASP8731, is a selective small molecule inhibitor of BACH1. We investigated the ability of ASP8731 to modulate pathways involved in SCD pathophysiology. In HepG2 liver cells, ASP8731 increased HMOX1 and FTH1 mRNA. In pulmonary endothelial cells, ASP8731 decreased VCAM1 mRNA in response to TNF-α and blocked a decrease in glutathione in response to hemin. Townes-SS mice were gavaged once per day for 4 weeks with ASP8731, hydroxyurea (HU) or vehicle. Both ASP8731 and HU inhibited heme-mediated microvascular stasis and in combination, ASP8731 significantly reduced microvascular stasis compared to HU alone. In Townes-SS mice, ASP8731 and HU markedly increased heme oxygenase-1 and decreased hepatic ICAM-1, NF-kB phospho-p65 protein expression in the liver, and white blood cell counts. In addition, ASP8731 increased gamma-globin expression and HbF+ cells (F-cells) as compared to vehicle-treated mice. In human erythroid differentiated CD34+ cells, ASP8731 increased HGB mRNA and increased the percentage of F-cells 2-fold in manner similar to HU. ASP8731 and HU when given together induced more HbF+ cells compared to either drug alone. In CD34+ cells from one donor that was non-responsive to HU, ASP8731 induced HbF+ cells ~2-fold. ASP8731 and HU also increased HBG and HBA, but not HBB mRNA in erythroid differentiated CD34+ cells derived from SCD patients. These data indicate that BACH1 may offer a new therapeutic target to treat SCD.
KW - BACH1
KW - HMOX1
KW - NF-kappa B
KW - Nrf2
KW - gamma globin
KW - hemoglobin F
KW - sickle cell disease
KW - vaso-occlusion
UR - http://www.scopus.com/inward/record.url?scp=85159918237&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85159918237&partnerID=8YFLogxK
U2 - 10.3389/fmed.2023.1101501
DO - 10.3389/fmed.2023.1101501
M3 - Article
C2 - 37144034
AN - SCOPUS:85159918237
SN - 2296-858X
VL - 10
JO - Frontiers in Medicine
JF - Frontiers in Medicine
M1 - 1101501
ER -