Cytotoxic Activity of the Mesoionic Compound MIH 2.4Bl in Breast Cancer Cell Lines

Luciana Amaral de Mascena Costa, Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Recife, Brazil.
Ashlyn C. Harmon, Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
Alvaro Aguiar Coelho Teixeira, Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Recife, Brazil.
Filipe Cássio Silva de Lima, Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Recife, Brazil.
Silvany de Sousa Araújo, Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Recife, Brazil.
Fabio Del Piero, Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.
Helivaldo Diógenes da Silva Souza, Department of Chemistry, Federal University of Paraíba, João Pessoa, Brazil.
Petrônio Filgueiras de Athayde Filho, Department of Chemistry, Federal University of Paraíba, João Pessoa, Brazil.
Severino Alves Junior, Department of Fundamental Chemistry, Federal University of Pernambuco, Recife, Brazil.
Maria de Mascena Diniz Maia, Department of Biology, Federal Rural University of Pernambuco, Recife, Brazil.
Aurea Wischral, Department of Veterinary Medicine, Federal Rural University of Pernambuco, Recife, Brazil.
Manoel Adrião Gomes Filho, Department of Morphology and Animal Physiology, Federal Rural University of Pernambuco, Recife, Brazil.
J Michael Mathis, Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA.

Document Type

Article

Publication Date

1-1-2020

Abstract

In this work, we report the synthesis of a new 1,3-thiazolium-5-thiolate derivative of a mesoionic compound (MIH 2.4Bl) and the characterization of its selective cytotoxicity on a panel of breast cancer cells lines. The cytotoxic effect of MIH 2.4Bl on breast cancer cell lines was determined by XTT and crystal violet assays, flow cytometry analysis, electron microscopy characterization, and terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) apoptosis assays. As determined using XTT cell growth and survival assays, MIH 2.4Bl exhibited growth inhibition activity on most breast cancer cell lines tested, compared with normal human mammary epithelial cells. Three breast cancer cell lines (MCF-7, T-47D, and ZR-75-1) showed a more potent sensitivity index to growth inhibition by MIH 2.4Bl than the other breast cancer cell lines. Interestingly, these 3 cell lines were derived from tumors of Luminal A origin and have ER (estrogen receptor), PR (progesterone receptor), and HER2 (human epidermal growth factor receptor 2) positive expression. Additional analysis of cytotoxicity mediated by MIH 2.4Bl was performed using the MCF-7 cell line. MCF-7 cells displayed both time- and dose-dependent decreases in cell growth and survival, with a maximum cytotoxic effect observed at 72 and 96 hours. The MCF-7 cells were also characterized for cell cycle changes upon treatment with MIH 2.4Bl. Using flow cytometry analysis of cell cycle distribution, a treatment-dependent effect was observed; treatment of cells with MIH 2.4Bl increased the G2/M population to 34.2% compared with 0.1% in untreated (control) cells. Ultrastructural analysis of MFC-7 cells treated with MIH 2.4Bl at 2 different concentrations (37.5 and 75 μM) was performed by transmission electron microscopy. Cells treated with 37.5 μM MIH 2.4Bl showed morphologic changes beginning at 6 hours after treatment, while cells treated with 75 μM showed changes beginning at 3 hours after treatment. These changes were characterized by an alteration of nuclear morphology and mitochondrial degeneration consistent with apoptotic cell death. Results of a TUNEL assay performed on cells treated for 96 hours with MIH 2.4Bl supported the observation of apoptosis. Together, these results suggest that MIH 2.4Bl is a promising candidate for treating breast cancer and support further in vitro and in vivo investigation.

Publication Source (Journal or Book title)

Breast cancer : basic and clinical research

First Page

1178223420913330

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