Antitumor effects of dicyanoaurate(I)-based complexes: In vivo and in silico insights using the HT29 xenograft model

• Three Au(I) complexes containing dicyanidoaurate(I) were synthesized and characterized. • The HT29 xenograft tumor model in CD1/Nude and Balb/C mice was used. • The Au(I) complexes suppress tumor growth but do not inhibit normal tissue functions, such as antioxidant enzyme activities . • The Au(I) complexes cause low expression of Bcl-2, CDK1, ABCC1 , and MDM2 or high expression of TP53, BAX, CASP3, and CASP8, resulting in increased apoptosis. • The Au(I) complexes interact with PI3K alpha, NRAS, BCL2, and TERT protein , exerting an antiproliferative feature in cells by suppressing cell proliferation . Colorectal adenocarcinoma, the second deadliest malignancy, is characterized by chromosomal instability and mismatch repair deficiencies, leading to apoptosis resistance. Previously, we developed Au(I) complexes [Ni( hydeten )Au 2 (CN) 4 ] ( C1 ), [Ni( bishydeten )Au 2 (CN) 4 ] ( C2 ), and [Cd( edbea ) 2 ][Au(CN) 2 ] 2 .H 2 O ( C3 ) that induce apoptosis in cancer cells without toxicity to normal cells in vitro . In this study, we evaluate the in vivo antitumor efficacy of these Au(I) complexes, assessing tumor volume, survival rate, and protein markers related to cell cycle, apoptosis, and oxidative stress through immunohistochemistry, gene expression, and ELISA assays. Molecular docking studies of the complexes with proteins revealed the best binding interactions. In molecular docking analysis, compounds C1, C2 , and C3 interacted with more than one target. The best interaction results were obtained with PI3K alpha target among these targets. E Total energy values presenting the docking score value on PI3K alpha (PDB ID: 5ITD ) were calculated as -1653.5 kJ/mol for C1 , -1863.4 kJ/mol for C2 , and -2420.4 kJ/mol for C3 . In the HT29 xenograft tumor model, treatment with Au(I) complexes (0.5 mg/kg) resulted in a significant reduction in tumor volume and increased survival. Histopathological analysis confirmed minimal side effects on tissues, while assessment of peroxidase (POD), superoxide dismutase (SOD), and catalase (CAT) levels indicated that the mechanism of action was not based on oxidative stress-induced cell death. Overall, Au(I) complexes demonstrated selective low toxicity and antitumor effects via apoptosis, suggesting their potential as therapeutic agents for colorectal adenocarcinoma.