IOX-101, a novel small molecule, reduces AML cell proliferation by Akt enzyme inhibition

Rajagopalan, Prasanna; Raju, M.R.; Aseeri, Hateem; Helal, Ismail M.; Elbessoumy, Ashraf A

doi:10.2298/abs170922049r

Cited by 4 publications

(3 citation statements)

References 25 publications

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“…Indane-1-ones are a class of small molecules with high drug-likeliness properties [9]. Several studies have proven Arylidene indan-1-ones to be effective against primary and resistant forms of cancers [10][11][12]. Therefore, the current investigation aims to screen one novel arylidene indanone analogue (FPMX-14) as an Akt inhibition target against renal carcinoma cells using computation and in vitro models.…”

Section: Introductionmentioning

confidence: 99%

Computational docking and in vitro analysis identifies novel arylidene analogue FPMXY-14 against renal cancer cells by attenuating Akt

Otifi¹,

Alshyarba²,

Fayi³

et al. 2021

Oncology Research

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Targeted therapies are gaining global attention to tackle Renal Cancer (RC). This study aims to screen FPMXY-14 (novel arylidene analogue) for Akt inhibition by computational and in vitro methods. FPMXY-14 was subjected to proton NMR analysis and Mass spectrum analysis. Vero, HEK-293, Caki-1, and A498 cell lines were used. Akt enzyme inhibition was studied with the fluorescent-based kit assay. Modeller 9.19, Schrodinger 2018-1, LigPrep module, and Glide docking were used in computational analysis. The nuclear status was assessed by PI/Hoechst-333258 staining, cell cycle, and apoptosis assays were performed using flow cytometry. Scratch wound and migrations assays were performed. Western blotting was applied to study key signalling proteins. FPMXY-14 selectively inhibited kidney cancer cell proliferation with GI 50 values of 77.5 nM and 101.40 nM in Caki-1 cells and A-498 cells, respectively. The compound dose-dependently inhibited Akt enzyme with an IC 50 value of 148.5 nM and bound efficiently at the allosteric pocking of the Akt when computationally analyzed. FPMXY-14 caused nuclear condensation/fragmentation, increased the sub G 0 /G 1 , G 2 M populations, and induced early, late phase apoptosis in both cells when compared to controls. Treatment of the compound inhibited wound healing and migration of tumor cells, while proteins like Bcl-2, Bax, and caspase 3 were also altered. FPMXY-14 effectively inhibited the phosphorylation of Akt in these cancer cells, while total Akt was unaltered. FPMXY-14 exhibited anti-proliferative and anti-metastatic activities in kidney cancer cells by attenuating the Akt enzyme. Further pre-clinical research on animals with a detailed pathway elucidation is recommended.

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Section: Introductionmentioning

confidence: 99%

Computational docking and in vitro analysis identifies novel arylidene analogue FPMXY-14 against renal cancer cells by attenuating Akt

Otifi¹,

Alshyarba²,

Fayi³

et al. 2021

Oncology Research

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“…AML is often characterized by myeloblast-induced clonal expansion [4]. As this form of the disease has a stem cellderived hematopoietic origin, uncontrolled accumulation of these cells can be fatal [5].…”

Section: Introductionmentioning

confidence: 99%

“…The expression of ERs in differentiated AML cells and aberrant hematopoiesis has been assessed. In contrast, inhibitors of Akt kinase can reportedly control the proliferation of AML cells [4]. However, targeting AML cells using a dual ER and Akt inhibitor has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

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

Shahrani¹,

Rajagopalan²,

Abohassan³

et al. 2021

Oncology Research

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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,6methyl, 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.

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IOX-101 Reverses Drug Resistance Through Suppression of Akt/mTOR/NF-κB Signaling in Cancer Stem Cell-Like, Sphere-Forming NSCLC Cell

2020

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Drug discovery research to fight lung cancer is incessantly challenged by drug resistance. In this study, we used drug-resistant lung cancer stem like cells (A549-CS) to compare the efficacy of standard drugs like cisplatin (DDP) and gemcitabine (GEM) with a novel arylidene derivative IOX-101. A549-CS was derived from regular A549 cells by growing in special media. Resistance proteins were detected using Western blotting. Cell proliferations were assessed by MTT assay. Cytokine release was enumerated using enzyme-linked immunosorbent assay. The effect of drugs on apoptosis and cell cycle was studied with flow cytometry protocols. Apoptosis-related proteins, caspases, and other signaling protein expressions like Akt and mammalian target of rapamycin (mTOR) were assessed by Western blotting. Expression of CD133 and nuclear factor κB (NF-κB) phosphorylation was assessed using flow cytometry. A549-CS showed significant increase in CD133 expression in comparison with A549 cells. Expression of resistance markers like MDR-1, lung resistance protein (LRP), and GST-II were detected in A549-CS. While DDP and GEM had relatively lower efficacy in A549-CS, IOX-101 inhibited the proliferation of both A549 and A549-CS with GI50 values of 268 and 296.5 nM, respectively. IOX-101 increased the sub-G0 phase in the cell cycle of A549-CS and increased the percentage of apoptotic cells. Western blot analysis revealed activation of caspases, Bax, and reduction in Bcl-2 levels. Further mechanistic investigation revealed IOX-101 to deactivate Akt, mTOR, and NF-κB signaling in A549-CS cells. Additionally, IOX-101 treatment to A549-CS also reversed MDR-1 and LRP expressions. Collectively, our results demonstrate efficacy of IOX-101 in A549-CS, which was resistant against the tested standard drugs. The activity was mediated by suppressing Akt/mTOR/NF-κB signaling.

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IOX-101, a novel small molecule, reduces AML cell proliferation by Akt enzyme inhibition

Cited by 4 publications

References 25 publications

Computational docking and in vitro analysis identifies novel arylidene analogue FPMXY-14 against renal cancer cells by attenuating Akt

Computational docking and in vitro analysis identifies novel arylidene analogue FPMXY-14 against renal cancer cells by attenuating Akt

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

IOX-101 Reverses Drug Resistance Through Suppression of Akt/mTOR/NF-κB Signaling in Cancer Stem Cell-Like, Sphere-Forming NSCLC Cell

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