Anticancer efficacy of 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),a novel,dual,estrogen receptor-Akt kinase inhibitor in acute myeloid leukemia cells  

作　　者：MESFER AL SHAHRANI PRASANNA RAJAGOPALAN MOHAMMAD ABOHASSAN MOHAMMAD ALSHAHRANI YASSER ALRAEY REEM MGAHTANI SURESH RADHAKRISHNAN KHLOOD DAGREERY 

机构地区：[1]Department of Clinical Laboratory Sciences,College of Applied Medical Sciences,King Khalid University,Abha,Saudi Arabia [2]Central Research Laboratory,College of Applied Medical Sciences,King Khalid University,Abha,Saudi Arabia [3]PG and Research Department of Chemistry,Presidency College,Chennai,Tamil Nadu,India [4]Regional Laboratory and Central Blood Bank,Jazan,Saudi Arabia

出　　处：《Oncology Research》2021年第3期149-157,共9页肿瘤学研究（英文）

摘　　要：Estrogen receptor(ER)αis expressed in a subset of patient-derived acute myeloid leukemia(AML)cells,whereas Akt is predominantly expressed in most types of AML.Targeting AML with dual inhibitors is a novel approach to combat the disease.Herein,we examined a novel small molecule,3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one(SBL-060),capable of targeting AML cells by inhibiting ERαand Akt kinase.The chemical properties of SBL-060 were identified by proton nuclear magnetic resonance(^(1)H-NMR),^(13)C-NMR,and mass spectroscopy.In silico docking was performed using an automated protocol with AutoDock-VINA.THP-1 and HL-60 cell lines were differentiated using phorbol 12-myristate 13-acetate.ERαinhibition was assessed using ELISA.The MTT assay assessed cell viability.Flow cytometry was performed for cell cycle,apoptosis,and p-Akt analyses.Chemical analysis identified the compound as 3-(4-isopropyl)benzylidene-8-ethoxy,6-methyl,chroman-4-one,which showed high binding efficacy toward ER,with aΔG_(binding) score of−7.4 kcal/mol.SBL-060 inhibited ERα,exhibiting IC50 values of 448 and 374.3 nM in THP-1 and HL-60 cells,respectively.Regarding inhibited cell proliferation,GI50 values of SBL-060 were 244.1 and 189.9 nM for THP-1 and HL-60 cells,respectively.In addition,a dose-dependent increase in sub G_(0)/G_(1) phase cell cycle arrest and total apoptosis was observed after treatment with SBL-060 in both cell types.SBL-060 also dose-dependently increased the p-Akt-positive populations in both THP-1 and HL-60 cells.Our results indicate that SBL-060 has excellent efficacy against differentiated AML cell types by inhibiting ER and Akt kinase,warranting further preclinical evaluations.

关 键 词：Akt kinase AML THP-1 HL-60 Estrogen receptor Benzylidene compounds 

分 类 号：R73[医药卫生—肿瘤]