Cu(II)-acylhydrazone complex, a potent and selective antitumor agent against human osteosarcoma: Mechanism of action studies over in vitro and in vivo models

BALSA, LUCIA M.; SOLERNÓ, LUISINA M.; RODRIGUEZ, MARIA R.; PARAJÓN-COSTA, BEATRIZ S.; GONZALEZ-BARÓ, ANA C.; ALONSO, DANIEL F.; GARONA, JUAN; LEÓN, IGNACIO E.

CHEMICO-BIOLOGICAL INTERACTIONS

ELSEVIER IRELAND LTD

Año: 2023 vol. 384

0009-2797

Osteosarcoma (OS) is a frequent bone cancer, affecting largely children and young adults. Cisplatin (CDDP) hasbeen efficacious in the treatment of different cancer such us OS but the development of chemoresistance andimportant side effects leading to therapeutic failure. Novel therapies including copper compounds have shown tobe 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 themolecular 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 significantlyimpaired cell viability in both models (IC50 2D: 2.1 ± 0.3 μM; 3D: 9.1 ± 1.0 μM) (p < 0.001). Additional cellstudies demonstrated the copper compound inhibits cell proliferation and conveys cells to apoptosis, determinedby flow cytometry. CuHL showed a great genotoxicity, evaluated by comet assay. Proteomic analysis by OrbitrapMass Spectometry identified 27 differentially expressed proteins: 17 proteins were found overexpressed and 10underexpressed in MG-63 cells after the CuHL treatment. The response to unfolded protein was the most affectedbiological process. In addition, in vivo antitumor effects of the compound were evaluated on human OS tumors xenografted innude mice. CuHL treatment, at a dose of 2 mg/kg i.p., given three times/week for one month, significantlyinhibited the progression of OS xenografts and was associated to a reduction in mitotic index and to an incrementof tumor necrosis (p < 0.01). Administration of standard-of-care cytotoxic agent CDDP, following the sametreatment schedule as CuHL, failed to impair OS growth and progression.