Laboratory of Biology of Aging (LABEN), Department of Gerontology, Federal University of São Carlos, São Carlos, SP.
Department of Pharmacy, Federal University of Sergipe, São José, SE, Brazil.
Anticancer Drugs. 2020 Jan;31(1):35-43. doi: 10.1097/CAD.0000000000000826.
Triple-negative breast cancer subtype is the most aggressive type of breast cancer due to the lack of specific therapeutic targets, having limited treatment options, low survival prognosis and high recurrence rates. In this work, we describe the effects of a semisynthetic derivative of [6]-gingerol (6G) called SSi6, produced by the addition of a 2,4-dinitrophenylhydrazine reagent on several aspects of triple-negative breast cancer biology. Human breast cancer cell lines MDA-MB-231 and MCF-10A were used in the experiments. MTT assays were used to detect cell viability. Cell cycle and apoptosis assay were analyzed using flow cytometer Accuri C6 and analysis of proteins as retinoblastoma Rb and kinases Cdk4/6 were analyzed by western blotting. SSi6 induced cytotoxic effects on triple-negative breast cancer cells, with higher selectivity when compared to the non-tumor MCF-10A cells. In addition, SSi6 inhibited migration and invasion of triple-negative breast cancer cells and was able to arrest cell cycle at the G1-phase, mainly by decreasing Cdk4/6-Rb axis levels. Therefore, SSi6 provoked the induction of apoptosis in triple-negative breast cancer cells. SSi6 was more efficient in producing these effects, compared to the original 6G natural product. This study may contribute to a better understanding of the effects of natural and semisynthetic products on the in-vitro metastatic processes in the MDA-MB-231 triple-negative breast cancer cell line. Additional, it can be useful to understand the effects of chemical modifications on already effective natural compounds aiming at the improvement of their bioactive properties, such as in the increase of the cytotoxic selectivity against tumor cells, compared to non-tumor ones.
三阴性乳腺癌亚型由于缺乏特定的治疗靶点，治疗选择有限，生存预后差，复发率高，是最具侵袭性的乳腺癌类型。在这项工作中，我们描述了一种[6]-姜烯的半合成衍生物（6G），称为 SSi6，它通过添加 2,4-二硝基苯肼试剂对三阴性乳腺癌生物学的几个方面产生影响。实验中使用了人乳腺癌细胞系 MDA-MB-231 和 MCF-10A。MTT 测定法用于检测细胞活力。使用流式细胞仪 Accuri C6 分析细胞周期和凋亡，通过蛋白质印迹法分析视网膜母细胞瘤 Rb 和激酶 Cdk4/6 的表达。SSi6 对三阴性乳腺癌细胞产生细胞毒性作用，与非肿瘤 MCF-10A 细胞相比，选择性更高。此外，SSi6 抑制三阴性乳腺癌细胞的迁移和侵袭，并能够使细胞周期停滞在 G1 期，主要通过降低 Cdk4/6-Rb 轴水平。因此，SSi6 诱导三阴性乳腺癌细胞凋亡。与天然 6G 产物相比，SSi6 更有效地产生这些作用。这项研究可能有助于更好地理解天然和半合成产物对 MDA-MB-231 三阴性乳腺癌细胞系体外转移过程的影响。此外，它对于理解化学修饰对已经有效的天然化合物的影响可能是有用的，例如，提高对肿瘤细胞的细胞毒性选择性，而对非肿瘤细胞则降低毒性选择性。
