Robles-Escajeda Elisa, Das Umashankar, Ortega Nora M, Parra Karla, Francia Giulio, Dimmock Jonathan R, Varela-Ramirez Armando, Aguilera Renato J
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.
Drug Discovery & Development Research Group, College of Pharmacy & Nutrition, University of Saskatchewan, 110 Science Place, Saskatoon, SK, S7N 5C9, Canada.
Cell Oncol (Dordr). 2016 Jun;39(3):265-77. doi: 10.1007/s13402-016-0272-x. Epub 2016 Feb 26.
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.
根据世界卫生组织（WHO）的数据，乳腺癌是全球影响女性的最常见癌症。在美国，预计约12.3%的女性会被诊断出患有各种类型的乳腺癌，其治疗反应率各不相同。因此，鉴定新型抗乳腺癌药物至关重要。
将1,5-二芳基-3-氧代-1,4-戊二烯基药效团引入多种细胞毒素中。使用活细胞生物成像方法，对所得的三种二烯酮2a、2b和2c在多种人乳腺癌衍生细胞系中进行抗肿瘤活性测试，包括三阴性MDA-MB-231细胞系及其转移变体。特别强调二烯酮2c，因为其抗癌活性及其导致细胞死亡的方式迄今尚未见报道。
我们发现所有三种二烯酮对所测试的乳腺癌衍生细胞系均表现出强大的细胞毒性，而对非癌性人乳腺细胞系MCF-10A的毒性则明显较低。二烯酮2b和2c在亚微摩尔浓度水平下表现出最大的选择性细胞毒性。我们发现这两种二烯酮以浓度依赖的方式诱导MDA-MB-231细胞中外膜磷脂酰丝氨酸外翻，表明它们的细胞毒性作用可能由凋亡介导。我们观察到二烯酮2c可诱导MDA-MB-231细胞中的线粒体去极化、半胱天冬酶-3激活、细胞周期紊乱和DNA片段化，这证实了这种可能性。
我们的研究结果表明，二烯酮2c利用线粒体/内源性途径在三阴性MDA-MB-231乳腺癌衍生细胞中引发凋亡。这一观察结果值得进一步评估二烯酮2c作为潜在抗乳腺癌药物的可能性。
