TY - JOUR
T1 - Cytotoxic Activity of the Mesoionic Compound MIH 2.4Bl in Breast Cancer Cell Lines
AU - Amaral de Mascena Costa, Luciana
AU - Harmon, Ashlyn C.
AU - Aguiar Coelho Teixeira, Alvaro
AU - Cássio Silva de Lima, Filipe
AU - de Sousa Araújo, Silvany
AU - Del Piero, Fabio
AU - Diógenes da Silva Souza, Helivaldo
AU - Filgueiras de Athayde Filho, Petrônio
AU - Alves Junior, Severino
AU - de Mascena Diniz Maia, Maria
AU - Wischral, Aurea
AU - Adrião Gomes Filho, Manoel
AU - Mathis, J. Michael
N1 - Funding Information:
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We acknowledge CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior) for an international scholarship through the Science without Borders program (88887.122971/2016-00), and research funding from the Louisiana State University School of Veterinary Medicine. These funders had no role in study design, data collection and analysis, decision to publish, or preparation and submission of the article.
Funding Information:
The authors thank the research and administrative staff in the Department of Comparative Biomedical Science at the Louisiana State University School of Veterinary Medicine (United States) and the Federal Rural University of Pernambuco (Brazil) for their assistance. The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: We acknowledge CAPES (Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior) for an international scholarship through the Science without Borders program (88887.122971/2016-00), and research funding from the Louisiana State University School of Veterinary Medicine. These funders had no role in study design, data collection and analysis, decision to publish, or preparation and submission of the article.
Publisher Copyright:
© The Author(s) 2020.
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Apoptosis
KW - MCF-7 cells
KW - breast cancer
KW - cancer therapy
KW - cell cycle
KW - mesoionic compound
UR - http://www.scopus.com/inward/record.url?scp=85087312173&partnerID=8YFLogxK
U2 - 10.1177/1178223420913330
DO - 10.1177/1178223420913330
M3 - Article
AN - SCOPUS:85087312173
SN - 1178-2234
VL - 14
JO - Breast Cancer: Basic and Clinical Research
JF - Breast Cancer: Basic and Clinical Research
ER -