Elisa Robles-Escajeda1, Umashankar Das2, Nora M Ortega1, Karla Parra1, Giulio Francia1, Jonathan R Dimmock2, Armando Varela-Ramirez3, Renato J Aguilera4. 1. Cytometry, Screening and Imaging Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA. 2. Drug Discovery & Development Research Group, College of Pharmacy & Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7N 5C9, Canada. 3. Cytometry, Screening and Imaging Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA. avarela2@utep.edu. 4. Cytometry, Screening and Imaging Core Facility, Border Biomedical Research Center, Department of Biological Sciences, the University of Texas at El Paso, 500 West University Avenue, El Paso, TX, 79968-0519, USA. raguilera@utep.edu.
Abstract
PURPOSE: According to the World Health Organization (WHO), breast cancer is the most common cancer affecting women worldwide. In the USA ~12.3 % of all women are expected to be diagnosed with various types of breast cancer, exhibiting varying degrees of therapeutic response rates. Therefore, the identification of novel anti-breast cancer drugs is of paramount importance. METHODS: The 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore was incorporated into a number of cytotoxins. Three of the resulting dienones, 2a, 2b and 2c, were tested for their anti-neoplastic potencies in a variety of human breast cancer-derived cell lines, including the triple negative MDA-MB-231 cell line and its metastatic variant, using a live-cell bio-imaging method. Special emphasis was put on dienone 2c, since its anti-cancer activity and its mode of inflicting cell death have so far not been reported. RESULTS: We found that all three dienones exhibited potent cytotoxicities towards the breast cancer-derived cell lines tested, whereas significantly lower toxicities were observed towards the non-cancerous human breast cell line MCF-10A. The dienones 2b and 2c exhibited the greatest selective cytotoxicity at submicromolar concentration levels. We found that these two dienones induced phosphatidylserine externalization in MDA-MB-231 cells in a concentration-dependent manner, suggesting that their cytotoxic effect might be mediated by apoptosis. This possibility was confirmed by our observation that the dienone 2c can induce mitochondrial depolarization, caspase-3 activation, cell cycle disruption and DNA fragmentation in MDA-MB-231 cells. CONCLUSION: Our findings indicate that dienone 2c uses the mitochondrial/intrinsic pathway to inflict apoptosis in triple negative MDA-MB-231 breast cancer-derived cells. This observation warrants further assessment of dienone 2c as a potential anti-breast cancer drug.
PURPOSE: According to the World Health Organization (WHO), breast cancer is the most common cancer affecting women worldwide. In the USA ~12.3 % of all women are expected to be diagnosed with various types of breast cancer, exhibiting varying degrees of therapeutic response rates. Therefore, the identification of novel anti-breast cancer drugs is of paramount importance. METHODS: The 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore was incorporated into a number of cytotoxins. Three of the resulting dienones, 2a, 2b and 2c, were tested for their anti-neoplastic potencies in a variety of humanbreast cancer-derived cell lines, including the triple negative MDA-MB-231 cell line and its metastatic variant, using a live-cell bio-imaging method. Special emphasis was put on dienone 2c, since its anti-cancer activity and its mode of inflicting cell death have so far not been reported. RESULTS: We found that all three dienones exhibited potent cytotoxicities towards the breast cancer-derived cell lines tested, whereas significantly lower toxicities were observed towards the non-cancerous human breast cell line MCF-10A. The dienones 2b and 2c exhibited the greatest selective cytotoxicity at submicromolar concentration levels. We found that these two dienones induced phosphatidylserine externalization in MDA-MB-231 cells in a concentration-dependent manner, suggesting that their cytotoxic effect might be mediated by apoptosis. This possibility was confirmed by our observation that the dienone 2c can induce mitochondrial depolarization, caspase-3 activation, cell cycle disruption and DNA fragmentation in MDA-MB-231 cells. CONCLUSION: Our findings indicate that dienone 2c uses the mitochondrial/intrinsic pathway to inflict apoptosis in triple negative MDA-MB-231breast cancer-derived cells. This observation warrants further assessment of dienone 2c as a potential anti-breast cancer drug.
Entities:
Keywords:
Anti-cancer drug discovery; Apoptosis; Caspase-3; Cell cycle; Curcumin analogues; DNA fragmentation; Mitochondrial depolarization
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