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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
Estrogen receptor (ER) α is 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-isoprop...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Tech Science Press
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10207952/ https://www.ncbi.nlm.nih.gov/pubmed/37304671 http://dx.doi.org/10.32604/or.2022.03539 |
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author | SHAHRANI, MESFER AL RAJAGOPALAN, PRASANNA ABOHASSAN, MOHAMMAD ALSHAHRANI, MOHAMMAD ALRAEY, YASSER GAHTANI, REEM M. RADHAKRISHNAN, SURESH DAGREERY, KHLOOD |
author_facet | SHAHRANI, MESFER AL RAJAGOPALAN, PRASANNA ABOHASSAN, MOHAMMAD ALSHAHRANI, MOHAMMAD ALRAEY, YASSER GAHTANI, REEM M. RADHAKRISHNAN, SURESH DAGREERY, KHLOOD |
author_sort | SHAHRANI, MESFER AL |
collection | PubMed |
description | Estrogen receptor (ER) α is 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 ERα and 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. ERα inhibition 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 a ΔG(binding) score of −7.4 kcal/mol. SBL-060 inhibited ERα, exhibiting IC(50) values of 448 and 374.3 nM in THP-1 and HL-60 cells, respectively. Regarding inhibited cell proliferation, GI(50) 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. |
format | Online Article Text |
id | pubmed-10207952 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Tech Science Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102079522023-06-10 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 SHAHRANI, MESFER AL RAJAGOPALAN, PRASANNA ABOHASSAN, MOHAMMAD ALSHAHRANI, MOHAMMAD ALRAEY, YASSER GAHTANI, REEM M. RADHAKRISHNAN, SURESH DAGREERY, KHLOOD Oncol Res Article Estrogen receptor (ER) α is 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 ERα and 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. ERα inhibition 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 a ΔG(binding) score of −7.4 kcal/mol. SBL-060 inhibited ERα, exhibiting IC(50) values of 448 and 374.3 nM in THP-1 and HL-60 cells, respectively. Regarding inhibited cell proliferation, GI(50) 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. Tech Science Press 2022-08-01 /pmc/articles/PMC10207952/ /pubmed/37304671 http://dx.doi.org/10.32604/or.2022.03539 Text en © 2021 Shahrani et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Article SHAHRANI, MESFER AL RAJAGOPALAN, PRASANNA ABOHASSAN, MOHAMMAD ALSHAHRANI, MOHAMMAD ALRAEY, YASSER GAHTANI, REEM M. RADHAKRISHNAN, SURESH DAGREERY, KHLOOD 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10207952/ https://www.ncbi.nlm.nih.gov/pubmed/37304671 http://dx.doi.org/10.32604/or.2022.03539 |
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