Laboratório de Farmacologia e Toxicologia Celular - FarmaTec, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
Instituto de Química, Universidade Federal de Goiás, Goiânia, GO, Brazil.
Eur J Pharm Sci. 2017 Sep 30;107:1-15. doi: 10.1016/j.ejps.2017.06.018. Epub 2017 Jun 13.
This study shows the design, synthesis and antitumoral potential evaluation of a novel chalcone-like compound, (E)-3- (3, 5-di-ter-butyl-4-hydroxyphenyl)-1- (4-hydroxy-3-methoxyphenyl) prop-2-en-1-one [LQFM064) (4)], against human breast adenocarcinoma MCF7 cells. Some toxicological parameters were also investigated. LQFM064) (4) exhibited cytotoxic activity against MCF7 cells (IC=21μM), in a concentration dependent-manner, and triggered significant changes in cell morphology and biochemical/molecular parameters, which are suggestive of an apoptosis inductor. LQFM064) (4) (21μM) induced cell cycle arrest at G0/G1 phase with increased p53 and p21 expressions. It was also shown that the compound (4) did not interfere directly in p53/MDM2 complexation of MCF7 cells. In these cells, externalization of phosphatidylserine, cytochrome c release, increased expression of caspases-7, -8 and -9, reduced mitochondrial membrane potential and ROS overgeneration were also detected following LQFM064 (4) treatment. Further analysis revealed the activation of both apoptotic pathways via modulation of the proteins involved in the extrinsic and intrinsic pathways with an increase in TNF-R1, Fas-L and Bax levels and a reduction in Bcl-2 expression. Furthermore, KIT proto-oncogene receptor tyrosine kinase, insulin-like growth factor (IGF1) and platelet-derived growth factor receptor A (PDGFRA) were downregulated, while glutathione S-transferase P1 (GSTP1) and interferon regulatory factor 5 (IRF5) expressions were increased by LQFM064 (4)-triggered cytotoxic effects in MCF7 cells. Moreover, it can be inferred that compound (4) has a moderate acute oral systemic toxicity hazard, since its estimated LD was 452.50mg/kg, which classifies it as UN GHS Category 4 (300mg/kg>LD<2000mg/kg). Furthermore, LQFM064 (4) showed a reduced potential myelotoxicity (IC=150μM for mouse bone marrow hematopoietic progenitors). In conclusion, LQFM064 (4) was capable of inducing breast cancer cells death via different cytotoxic pathways. Thus, it is a promising alternative for the treatment of neoplasias, especially in terms of the drug resistance development.
本研究设计、合成并评价了一种新型查尔酮类似物（E）-3-（3,5-二-叔丁基-4-羟基苯基）-1-（4-羟基-3-甲氧基苯基）-2-丙烯-1-酮[LQFM064)（4)]（4））对人乳腺癌 MCF7 细胞的抗肿瘤潜力。还研究了一些毒理学参数。LQFM064)（4）对 MCF7 细胞表现出细胞毒性活性（IC=21μM），呈浓度依赖性，并导致细胞形态和生化/分子参数发生显著变化，提示诱导细胞凋亡。LQFM064)（4）（21μM）诱导细胞周期停滞在 G0/G1 期，同时增加了 p53 和 p21 的表达。还表明该化合物（4）不会直接干扰 MCF7 细胞中 p53/MDM2 复合物的形成。在这些细胞中，在 LQFM064（4）处理后，还检测到磷脂酰丝氨酸外翻、细胞色素 c 释放、caspase-7、-8 和 -9 的表达增加、线粒体膜电位降低和 ROS 过度产生。进一步分析表明，通过调节外源性和内源性途径中涉及的蛋白，激活了两种凋亡途径，同时增加了 TNF-R1、Fas-L 和 Bax 的水平，并降低了 Bcl-2 的表达。此外，KIT 原癌基因受体酪氨酸激酶、胰岛素样生长因子（IGF1）和血小板衍生生长因子受体 A（PDGFRA）被下调，而谷胱甘肽 S-转移酶 P1（GSTP1）和干扰素调节因子 5（IRF5）的表达被上调。由 LQFM064（4）诱导的 MCF7 细胞的细胞毒性作用。此外，可以推断化合物（4）具有中度急性口服全身毒性危害，因为其估计 LD 为 452.50mg/kg，这将其归类为 UN GHS 类别 4（300mg/kg>LD<2000mg/kg）。此外，LQFM064（4）显示出降低的潜在骨髓毒性（对小鼠骨髓造血祖细胞的 IC=150μM）。总之，LQFM064（4）能够通过不同的细胞毒性途径诱导乳腺癌细胞死亡。因此，它是治疗肿瘤的一种有前途的替代方法，尤其是在药物耐药性发展方面。
