New copper(ii) and oxidovanadium(iv) complexes with a vitamin B₆ Schiff base: mechanism of action and synergy studies on 2D and 3D human osteosarcoma cell models

We report the synthesis, characterization and anticancer activity of a new Schiff base (H2L) derived from the condensation of pyridoxamine with pyridoxal and its novel copper(ii) and oxidovanadium(iv) complexes: [Cu(HL)Cl] (1), [Cu(LH2)(phen)]Cl-2 (2), [Cu(LH2)(amphen)]Cl-2 (3), [(VO)-O-IV(HL)Cl] (4), and [(VO)-O-IV(LH2)(phen)]Cl-2 (5), where phen is 1,10-phenanthroline and amphen is its 5-amino derivative. All compounds were characterized by analytical and spectroscopic techniques, namely FTIR, UV-vis and EPR spectroscopy. Their stability in aqueous media was evaluated, revealing that the presence of the phen co-ligand significantly increases the stability. The ternary Cu(ii) complexes (2 and 3) impaired cell viability of osteosarcoma cells (MG-63) (IC50 values of 3.6 +/- 0.6 and 7 +/- 1.9 mu M for 2 and 3), while 1 and the (VO)-O-IV complexes did not show relevant anticancer activity. Complexes 2 and 3 are also more active than cisplatin (CDDP). Synergistic studies between 2 and sorafenib showed significant synergism on MG-63 cells for the following combinations: 2 (2.0 mu M) + sorafenib (10.0 mu M) and 2 (2.5 mu M) + sorafenib (12.5 mu M), whilst the combination of 2 and CDDP did not show synergy. Complex 2 interacts with DNA, inducing significant genotoxic effects on MG-63 cells from 1.0 to 2.5 mu M and it increases the ROS levels 880% over basal. Moreover, 2 induces apoptosis at 1.0 and 2.0 mu M, while its combination with sorafenib induces apoptosis and necrosis. Finally, compound 2 reduces the cell viability of MG-63 spheroids showing an IC50 value 7-fold lower than that of CDDP (8.5 +/- 0.4 mu M vs. 65 +/- 6 mu M). The combination of 2 and sorafenib also showed synergism on spheroids, suggesting that the combination of these drugs improves the anticancer effect against bone cancer cells.