The Schiff base hydrazine copper(II) complexes induce apoptosis by P53 overexpression and prevent cell migration through protease-independent pathways

Although chemotherapy has increased the life expectancy of cancer patients, its toxic side effects remain a major challenge. Recently, organometallic compounds, such as Schiff base copper complexes, have become promising candidates for next-generation anticancer drugs owing to their unique anticancer activities. In this study, binuclear copper(II) complex-1 and mononuclear copper(II) complex-2 were examined to analyze their anticancer mechanisms further. For this purpose, a viability test, flow cytometry analysis of apoptosis and the cell cycle, migration assay, and gene expression analysis were performed. According to our results, complex-1 was more cytotoxic than complex-2 at 24/48-h intervals. Our findings also demonstrated that both complexes induced apoptosis at IC50 concentrations and arrested the cell cycle at the G1-S checkpoint. However, complex-1 accelerates cell cycle arrest at the sub-G0/G1 phase more than complex-2 does. Furthermore, gene expression analysis showed that only complex-1 induces the expression of p53. Interestingly, both complexes induced Bcl-2 overexpression. However, they did not affect MMP-13 expression. More interestingly, both complexes inhibited cell migration in different ways, including amoeboid and collective, by recruiting protease-independent pathways. This study confirmed that adding several metal cores and co-ligands increased the activity of the complex. It also appeared that Cu-containing complexes could prevent the migration of cancer cells through protease-independent pathways, which can be used for novel therapeutic purposes.

Automated summary

Although chemotherapy has extended the life expectancy of cancer patients, the toxic side effects of chemotherapy are still a major challenge. Organometallic compounds, specifically Schiff base copper complexes, have emerged as promising candidates for next-generation anticancer drugs due to their unique anticancer activities. This study examined the anticancer mechanisms of two copper(II) complexes, binuclear complex-1 and mononuclear complex-2. The results showed that complex-1 exhibited higher cytotoxicity than complex-2. Both complexes induced apoptosis and cell cycle arrest, but complex-1 showed a stronger effect on cell cycle arrest at the sub-G0/G1 phase. Furthermore, gene expression analysis revealed that only complex-1 induced the expression of p53 while both complexes induced Bcl-2 overexpression. Interestingly, both complexes inhibited cell migration through protease-independent pathways. This study highlights the potential of Cu-containing complexes in preventing cancer cell migration and suggests their use in novel therapeutic approaches.