Open Access

ARTICLE

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

by MESFER AL SHAHRANI^1,2,*, PRASANNA RAJAGOPALAN^1,2, MOHAMMAD ABOHASSAN¹, MOHAMMAD ALSHAHRANI¹, YASSER ALRAEY¹, REEM M. GAHTANI¹, SURESH RADHAKRISHNAN³, KHLOOD DAGREERY⁴

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

* Corresponding Author: Mesfer Al Shahrani,

Oncology Research 2021, 29(3), 149-157. https://doi.org/10.32604/or.2022.03539

Received 27 January 2022; Accepted 19 July 2022; Issue published 01 August 2022

Abstract

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), ¹³C-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 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 G₀/G₁ 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.

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