Resumen:
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,
H(2)L=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 (IC(50) 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.
