Heterobimetallic Ru(ii)/Fe(ii) complexes as potent anticancer agents against breast cancer cells, inducing apoptosis through multiple targets.,Metallomics

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Heterobimetallic Ru(ii)/Fe(ii) complexes as potent anticancer agents against breast cancer cells, inducing apoptosis through multiple targets.
Metallomics ( IF 2.9 ) Pub Date : 2020-02-28 , DOI: 10.1039/c9mt00272c
Adriana Pereira Mundim Guedes ₁ , Francyelli Mello-Andrade , Wanessa Carvalho Pires , Maria Alice Montes de Sousa , Paula Francinete Faustino da Silva , Mariana S de Camargo , Hendryk Gemeiner , Menegário A Amauri , Clever Gomes Cardoso , Paulo Roberto de Melo Reis , Elisângela de Paula Silveira-Lacerda , Alzir A Batista

Affiliation

Antimetastatic activity, high selectivity and cytotoxicity for human tumor cell lines make ruthenium(ii) complexes attractive for the development of new chemotherapeutic agents for cancer treatment. In this study, cytotoxic activities and the possible mechanism of cell death induced by three ruthenium complexes were evaluated, [Ru(MIm)(bipy)(dppf)]PF6 (1), [RuCl(Im)(bipy)(dppf)]PF6 (2) and [Ru(tzdt)(bipy)(dppf)]PF6 (3). The results showed high cytotoxicity and selectivity indexes for the human triple-negative breast tumor cell line (MDA-MB-231) with IC50 value and selectivity index for complex 1 (IC50 = 0.33 ± 0.03 μM, SI = 4.48), complex 2 (IC50 = 0.80 ± 0.06 μM, SI = 2.31) and complex 3 (IC50 = 0.48 ± 0.02 μM, SI = 3.87). The mechanism of cell death induced in MDA-MB-231 cells, after treatment with complexes 1-3, indicated apoptosis of the cells as a consequence of the increase in the percentage of cells in the Sub-G1 phase in the cell cycle analysis, characteristic morphological changes and the presence of apoptotic cells labeled with Annexin-V. Multiple targets of action were identified for complexes 1 and 3 with an induction of DNA damage in cells treated with complexes 1 and 3, mitochondrial depolarization with a reduction in mitochondrial membrane potential, an increase in reactive oxygen species levels and increased expression levels of caspase 3 and p53. In addition, antimetastatic activities for complexes 1 and 3 were observed by inhibition of cell migration by the wound healing assay and Boyden chamber assay, as well as inhibition of angiogenesis caused by MDA-MB-231 tumor cells in the CAM model.

中文翻译：

异双金属Ru（ii）/ Fe（ii）复合物可作为有效的抗乳腺癌细胞抗癌剂，通过多个靶标诱导细胞凋亡。

对人类肿瘤细胞系的抗转移活性，高选择性和细胞毒性使钌（ii）复合物对开发用于癌症治疗的新型化学治疗剂具有吸引力。在这项研究中，评估了三种钌络合物[Ru（MIm）（bipy）（dppf）] PF6（1），[RuCl（Im）（bipy）（dppf）]诱导的细胞毒性活性和细胞死亡的可能机制。 PF6（2）和[Ru（tzdt）（bipy）（dppf）] PF6（3）。结果显示，对于人类三阴性乳腺癌细胞系（MDA-MB-231）具有高的细胞毒性和选择性指数，对于复合物1（IC50 = 0.33±0.03μM，SI = 4.48），复合物2（IC50 = 0.33±0.03μM，IC50值和选择性指数） IC50 = 0.80±0.06μM，SI = 2.31）和复合物3（IC50 = 0.48±0.02μM，SI = 3.87）。复合物1-3处理后，MDA-MB-231细胞诱导的细胞死亡机制，由于细胞周期分析中Sub-G1期细胞百分比的增加，特征性形态学变化以及膜联蛋白-V标记的凋亡细胞的存在，表明细胞凋亡。确定了复合物1和3的多个作用靶点，这些复合物诱导了复合物1和3处理的细胞中的DNA损伤，线粒体去极化，线粒体膜电位降低，活性氧水平增加和caspase 3表达水平增加和p53。另外，通过伤口愈合测定法和博登室测定法抑制细胞迁移，以及在CAM模型中抑制由MDA-MB-231肿瘤细胞引起的血管生成，观察到复合物1和3的抗转移活性。

更新日期：2020-02-19

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