A novel curcumin-like dienone induces apoptosis in triple-negative breast cancer cells
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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.
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.
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.
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.
KeywordsAnti-cancer drug discovery Apoptosis Caspase-3 Cell cycle DNA fragmentation Mitochondrial depolarization Curcumin analogues
Funding for this work was provided by the National Institute of General Medical Sciences-Support of Competitive Research grant 1SC3GM103713-03 to RJA, as well as a Canadian Institutes of Health Research-Regional Partnerships Program Saskatchewan grant to JRD and UD. The authors also thank the Cytometry, Screening and Imaging Core Facility at the University of Texas at El Paso (UTEP), which was supported by a Research Centers in Minority Institutions program grant 2G12MD007592 to the Border Biomedical Research Center in UTEP from the National Institute on Minority Health and Health Disparities, a component of National Institutes of Health. The authors thank Gladys Almodovar and Sarah T. Baca (both with UTEP) for critical reviews of the manuscript and cell culture expertise, and to Drs. Karen Carr and John Norman (both with Beckman Coulter) for advice and instructions on the cell-cycle protocol, and also for the generous gift of the NIM-DAPI reagent. NMO, KP and ER-E were supported by NIGMS RISE training grant R25 GM069621-12. NMO was also supported by a Maximizing Access to Research Careers U*STAR program grant 2T34GM008048. KP was supported by the Student Mentoring to Achieve Retention: Triads in Science (SMARTS) program from National Science Foundation, grant DUE-1153832.
Compliance with Ethical Standards
Conflict of Interest
The authors declare no conflict of interest.
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