Herein, we report the synthesis, characterization and anticancer activity of six novel complexes of non-steroidal anti-inflammatory drug niflumic acid with Co(II) and Ni(II). In vitro cytotoxicity screening in MCF-7, HepG2 and HT-29 cancer cell lines showed that the complex 3 [Co(nif)₂(met)(4-pic)] and complex 6 [Ni(nif)₂(met)(4-pic)] among all the complexes exhibited the highest cytotoxicity against MCF-7 cells with IC₅₀ values of 11.14 µM and, 41.47 µM, respectively. Besides, all the complexes exhibited significantly higher selectivity towards mouse fibroblast 3T3L1 cells. Further mechanistic studies with both complexes on MCF-7 cells revealed their cytotoxic action through the mitochondrial-dependent apoptotic pathway causing an increase oxidative/nitrosative stress, decrease in mitochondrial membrane potential (ΔΨm), inducing the multicaspase activation and arresting the cell cycle at S phase. q-PCR analysis resulted in an increase in the expression of the apoptotic marker proteins bax, p53 and caspase-3 and -8 in MCF-7 cells, but a decrease in the expression of antiapoptotic bcl-2 gene. Moreover, both complexes induced the apoptosis through the inhibition of PI3K/Akt signaling pathway by decreasing the expression of PI3K and increasing dephosphorylation form of Akt protein. These results provide a significant contribution to the explanation of the anticancer mechanisms of these complexes in MCF-7 cells.

在此，我们报道了非甾体抗炎药尼氟酸与Co(II)和Ni(II)的六种新型复合物的合成、表征和抗癌活性。 MCF-7、HepG2 和 HT-29 癌细胞系的体外细胞毒性筛选表明，复合物3 [Co(nif) ₂ (met)(4-pic)] 和复合物6 [Ni(nif) ₂ (met)( 4-pic)]在所有复合物中对MCF-7细胞表现出最高的细胞毒性，IC ₅₀值分别为11.14 µM和41.47 µM。此外，所有复合物对小鼠成纤维细胞3T3L1细胞均表现出显着更高的选择性。对 MCF-7 细胞上这两种复合物的进一步机制研究揭示了它们通过线粒体依赖性细胞凋亡途径的细胞毒性作用，导致氧化/亚硝化应激增加，线粒体膜电位 (ΔΨm) 降低，诱导多半胱天冬酶激活并将细胞周期阻滞在 S阶段。 q-PCR分析结果显示MCF-7细胞中凋亡标记蛋白bax、p53以及caspase-3和-8的表达增加，但抗凋亡bcl-2基因的表达减少。此外，两种复合物均通过降低 PI3K 的表达和增加 Akt 蛋白的去磷酸化形式来抑制 PI3K/Akt 信号通路，从而诱导细胞凋亡。这些结果为解释这些复合物在 MCF-7 细胞中的抗癌机制做出了重大贡献。