Osteosarcoma (OS) is a frequent
bone cancer, affecting largely children and young adults.
Cisplatin (CDDP) has been efficacious in the treatment of different
cancer such us OS but the development of chemoresistance and important side effects leading to therapeutic failure. Novel
therapies including
copper compounds have shown to be potentially effective as anticancer drugs and one alternative to usually employed
platinum compounds. The goal of this work is the evaluation of the in vitro and in vivo antitumoral activity and dilucidate the molecular target of a Cu(II) cationic complex containing a tridentate
hydrazone ligand, CuHL for short, H2L=N'-'-(2-hydroxy-3-methoxybenzylidene)
thiophene-2-
carbohydrazide, against human OS MG-63 cells. Anticancer activity on MG-63 cell line was evaluated in OS monolayer and spheroids. CuHL significantly impaired cell viability in both models (IC50 2D: 2.1 ± 0.3 μM; 3D: 9.1 ± 1.0 μM) (p < 0.001). Additional cell studies demonstrated the
copper compound inhibits cell proliferation and conveys cells to apoptosis, determined by flow cytometry. CuHL showed a great genotoxicity, evaluated by comet assay. Proteomic analysis by Orbitrap Mass Spectometry identified 27 differentially expressed
proteins: 17
proteins were found overexpressed and 10 underexpressed in MG-63 cells after the CuHL treatment. The response to unfolded
protein was the most affected biological process. In addition, in vivo antitumor effects of the compound were evaluated on human OS
tumors xenografted in nude mice. CuHL treatment, at a dose of 2 mg/kg i.p., given three times/week for one month, significantly inhibited the progression of OS xenografts and was associated to a reduction in mitotic index and to an increment of
tumor necrosis (p < 0.01). Administration of standard-of-care
cytotoxic agent CDDP, following the same treatment schedule as CuHL, failed to impair OS growth and progression.