Cytotoxic Activity, Apoptosis Induction and Cell Cycle Arrest in Human Breast Cancer (MCF7) Cells by a Novel Fluorinated Tetrahydro-[1,2,4]Triazolo[3,4-a]Isoquinolin Chalcones

Magda F Mohamed,Nada S Ibrahim,Sherif Abdelaziz Ibrahim,May A El-Manawaty,Salwa M El-Hallouty,Hamdi M Hassaneen,Ismail A Abdelhamid

doi:10.1080/10406638.2021.2014535

Magda F Mohamed, Nada S Ibrahim + Show 5 more

Open Access

https://doi.org/10.1080/10406638.2021.2014535

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Abstract

A series of fluorinated chalcones (3a-f) was synthesized and confirmed by several spectral tools. The cytotoxic effect of this series was tested against a panel of different cancer cell lines (MCF7, A549, HCT116, and PC3). MTT assay revealed that chalcone 3f has the potent cytotoxic activity against all tested cancer cell lines except A549 cells. Chalcone 3f showed the least cytotoxic activity against the normal epithelial cell line RPE-1 and the lowest IC50 at 10.96 µM relative to the IC50 of doxorubicin at 12.8 µM against the human breast cancer cell line MCF7. Molecular docking studies showed a good interaction of chalcone 3f with the active site of histone demethylase (PLU-1/JARID1B) and Carboxy-terminal binding protein1 (CtBP1) proteins. Mechanistically, chalcone 3f induced cell cycle arrest at G2/M phase and apoptosis assessed by flow cytometry, as well as DNA fragmentation in MCF7 cells. Chalcone 3f upregulated mRNA expression levels of the apoptotic genes BAX, p53, and Caspase-7, Caspase-8, and Caspase-9, whereas mRNA expression levels of the antiapoptotic gene Bcl2, metastasis-related gene matrix metalloproteinase 1 (MMP1), and the autophagic markers ATG5 and LC3B were downregulated as quantified by qPCR. This study shows a cytotoxic effect of chalcone 3f against cancer cells and emerges as a promising therapeutic drug against breast cancer.

Highlights

Breast cancer is the second leading cause of cancer-related death among females worldwide with approximately 1.67 million new cancer cases (25% of all cancer cases) [1]
The anticancer activity of the synthesized compounds was studied against breast, lung, colon, and prostate cancer cells, including MCF7, A549, HCT116, and PC3, respectively, and the normal human retinal epithelial cell line RPE-1
Since we proved that chalcone 8 is an apoptosis inducer, we tested its impact on DNA fragmentation. as shown in Table 2 and Fig. 9, When MCF7 cells were treated with 10.96 μM of chalcone 8 for 48 h, the percentage of fragmented DNA was increased approximately by 6-fold (26.83%) in comparison to negative control MCF7 cells (4.56%)

Summary

Introduction

Breast cancer is the second leading cause of cancer-related death among females worldwide with approximately 1.67 million new cancer cases (25% of all cancer cases) [1]. The currently available treatments used for breast cancer include surgery and/or radiotherapy and adjuvant chemo- or hormone therapies [2]. Chalcones (1, 3-diphenyl-2-propene-1-one) are one of the important classes of anticancer agents that have a promising effect against breast cancer [4] They are the precursors of flavonoids and isoflavonoids and are found abundantly in edible plants [5]. Halogenated chalcones showed an enhanced anti-proliferative activity including arresting of the cell cycle, induction of apoptosis, and multidrug resistance (MDR) reversal activity [9, 10]. These findings prompted us to synthesize a novel series of halogenated chalcones and evaluate their cytotoxic activity against cancer cells with deciphering the underlying molecular mechanism of their action

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