Lima Aliny Pereira, Pereira Flávia Castro, Almeida Marcio Aurelio Pinheiro, Mello Francyelli Mariana Santos, Pires Wanessa Carvalho, Pinto Thallita Monteiro, Delella Flávia Karina, Felisbino Sérgio Luis, Moreno Virtudes, Batista Alzir Azevedo, de Paula Silveira-Lacerda Elisângela
Laboratory of Molecular Genetics and Cytogenetics, Institute of Biological Sciences, University Federal of Goiás-UFG, Goiânia, Goiás, Brazil.
Coordination of Science and Technology, University Federal of Maranhão, São Luís, Maranhão, Brazil.
PLoS One. 2014 Oct 17;9(10):e105865. doi: 10.1371/journal.pone.0105865. eCollection 2014.
Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas.
在过去的几十年里，钌配合物在抗肿瘤治疗中备受关注。钌是一种过渡金属，在合理的抗肿瘤药物设计和生物学应用方面具有诸多优势。在本研究中，对五种含氨基酸的钌配合物进行了体外研究，以确定它们对肉瘤-180肿瘤细胞的生物活性。通过MTT法评估了配合物的细胞毒性，并研究了其作用机制。结果表明，这五种配合物均抑制了S180肿瘤细胞系的生长，IC50值在22.53 μM至50.18 μM之间，且对正常L929成纤维细胞显示出低细胞毒性。流式细胞术分析显示，[Ru(gly)(bipy)(dppb)]PF6配合物（2）通过诱导凋亡抑制肿瘤细胞生长，Annexin V阳性细胞数量增加和G0/G1期细胞周期阻滞证明了这一点。进一步研究表明，配合物2导致线粒体膜电位丧失；激活了半胱天冬酶3、半胱天冬酶-8和半胱天冬酶-9，并导致半胱天冬酶3、半胱天冬酶-9以及bax基因的mRNA表达水平发生变化。促凋亡Bcl-2家族蛋白Bak的水平升高。因此，我们证明了钌氨基酸配合物是对抗S180肿瘤细胞的有前景的药物，我们建议进一步研究它们作为肉瘤化疗药物的作用。
