Mello-Andrade Francyelli, da Costa Wanderson Lucas, Pires Wanessa Carvalho, Pereira Flávia de Castro, Cardoso Clever Gomes, Lino-Junior Ruy de Souza, Irusta Vicente Raul Chavarria, Carneiro Cristiene Costa, de Melo-Reis Paulo Roberto, Castro Carlos Henrique, Almeida Marcio Aurélio Pinheiro, Batista Alzir Azevedo, Silveira-Lacerda Elisângela de Paula
1 Laboratório de Genética Molecular e Citogenética, Departamento de Genética, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Brazil.
2 Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Brazil.
Tumour Biol. 2017 Oct;39(10):1010428317695933. doi: 10.1177/1010428317695933.
Peritoneal carcinomatosis is considered as a potentially lethal clinical condition, and the therapeutic options are limited. The antitumor effectiveness of the [Ru(l-Met)(bipy)(dppb)]PF(1) and the [Ru(l-Trp)(bipy)(dppb)]PF(2) complexes were evaluated in the peritoneal carcinomatosis model, Ehrlich ascites carcinoma-bearing Swiss mice. This is the first study that evaluated the effect of Ru(II)/amino acid complexes for antitumor activity in vivo. Complexes 1 and 2 (2 and 6 mg kg) showed tumor growth inhibition ranging from moderate to high. The mean survival time of animal groups treated with complexes 1 and 2 was higher than in the negative and vehicle control groups. The induction of Ehrlich ascites carcinoma in mice led to alterations in hematological and biochemical parameters, and not the treatment with complexes 1 and 2. The treatment of Ehrlich ascites carcinoma-bearing mice with complexes 1 and 2 increased the number of Annexin V positive cells and cleaved caspase-3 levels and induced changes in the cell morphology and in the cell cycle phases by induction of sub-G1 and G0/G1 cell cycle arrest. In addition, these complexes reduce angiogenesis induced by Ehrlich ascites carcinoma cells in chick embryo chorioallantoic membrane model. The treatment with the LAT1 inhibitor decreased the sensitivity of the Ehrlich ascites carcinoma cells to complexes 1 and 2 in vitro-which suggests that the LAT1 could be related to the mechanism of action of amino acid/ruthenium(II) complexes, consequently decreasing the glucose uptake. Therefore, these complexes could be used to reduce tumor growth and increase mean survival time with less toxicity than cisplatin. Besides, these complexes induce apoptosis by combination of different mechanism of action.
腹膜癌病被认为是一种潜在致命的临床病症，治疗选择有限。在携带艾氏腹水癌的瑞士小鼠腹膜癌病模型中评估了[Ru(l - Met)(bipy)(dppb)]PF(1)和[Ru(l - Trp)(bipy)(dppb)]PF(2)配合物的抗肿瘤效果。这是第一项评估Ru(II)/氨基酸配合物体内抗肿瘤活性作用的研究。配合物1和2（2和6 mg/kg）显示出从中度到高度的肿瘤生长抑制作用。用配合物1和2处理的动物组的平均存活时间高于阴性对照组和赋形剂对照组。小鼠艾氏腹水癌的诱导导致血液学和生化参数的改变，而不是配合物1和2的治疗导致的。用配合物1和2处理携带艾氏腹水癌的小鼠增加了膜联蛋白V阳性细胞的数量和裂解的半胱天冬酶 - 3水平，并通过诱导亚G1和G0/G1细胞周期停滞诱导细胞形态和细胞周期阶段的变化。此外，这些配合物在鸡胚绒毛尿囊膜模型中减少了艾氏腹水癌细胞诱导的血管生成。用LAT1抑制剂处理降低了艾氏腹水癌细胞在体外对配合物1和2的敏感性，这表明LAT1可能与氨基酸/钌(II)配合物的作用机制有关，从而降低葡萄糖摄取。因此，这些配合物可用于减少肿瘤生长并增加平均存活时间，且毒性比顺铂小。此外，这些配合物通过不同作用机制的组合诱导细胞凋亡。
