Abstract
Background: Cancer remains one of the leading causes of mortality worldwide, with malignant melanoma posing a particularly significant clinical challenge owing to its highly aggressive and metastatic behaviour. Although current treatment modalities have demonstrated therapeutic benefit, their long-term effectiveness is frequently limited by the development of drug resistance, off-target toxicity, and adverse side effects. Consequently, there is a growing need for alternative therapeutic strategies that are effective against melanoma cells and less toxic to non-malignant tissues. Metal-based complexes have emerged as promising candidates in anticancer drug development, with cisplatin representing a notable clinical success; however, its use is constrained by severe systemic toxicity. In this context, the present study synthesised, characterized, and evaluated three novel copper(I) thiocyanate 4-methoxyphenyl phosphine complexes (VK 1, VK2 and VK3) for their anticancer activity against human malignant melanoma (A375) cells.
Methodology: The three copper(I) complexes were synthesized at varying metal-to-ligand ratios (1:1, 1:2 and 1:3) and characterized using spectroscopic and analytical techniques to confirm successful coordination and structural integrity. The cytotoxic effects of the complexes were assessed in A375 melanoma cells and compared with the standard chemotherapeutic agent cisplatin. Selectivity was evaluated using a non-malignant HEK293 cell line, while the mode of cell death induced by the most active complex was investigated using complementary morphological, biochemical, and mitochondrial function assays.
Key findings: All synthesized copper(I) complexes exhibited dose-dependent antiproliferative activity against A375 melanoma cells. Among them, VK 2 emerged as the most potent compound, with an IC50 value of 16.59 ± 6.00 μM, outperforming cisplatin under the same experimental conditions. Importantly, VK 2 demonstrated reduced cytotoxicity toward non-malignant HEK293 cells, yielding an IC50 value of 35.24 ± 3.56 μM and a favourable selectivity index of 2.12. Further biological evaluation revealed that VK 2 induced characteristic features of apoptotic cell death, including cell shrinkage, membrane blebbing, nuclear condensation, and a significant dose-dependent increase in caspase-3/7 activity. Mitochondrial function analysis showed a marked reduction in intracellular ATP levels under oxidative phosphorylation conditions without compromising mitochondrial membrane integrity, indicating involvement of a mitochondrial-mediated apoptotic pathway.
Conclusion: This study identifies VK 2 as a promising copper(I)-based complex with selective antiproliferative and pro-apoptotic activity against malignant melanoma cells. The findings highlight the potential of copper(I) complexes as alternative metal-based anticancer agents and support further investigation of VK 2 through expanded mechanistic studies and in vivo validation to assess its therapeutic potential.