RESUMO
Interest in the third-row transition metal osmium and its compounds as potential anticancer agents has grown in recent years. Here, we synthesized the osmium(VI) nitrido complex Na[OsVI(N)(tpm)2] (tpm = [5-(Thien-2-yl)-1H-pyrazol-3-yl]methanol), which exhibited a greater inhibitory effect on the cell viabilities of the cervical, ovarian, and breast cancer cell lines compared with cisplatin. Proteomics analysis revealed that Na[OsVI(N)(tpm)2] modulates the expression of protein-transportation-associated, DNA-metabolism-associated, and oxidative-stress-associated proteins in HepG2 cells. Perturbation of protein expression activity by the complex in cancer cells affects the functions of the mitochondria, resulting in high levels of cellular oxidative stress and low rates of cell survival. Moreover, it caused G2/M phase cell cycle arrest and caspase-mediated apoptosis of HepG2 cells. This study reveals a new high-valent osmium complex as an anticancer agent candidate modulating protein homeostasis.
Assuntos
Antineoplásicos , Osmio , Humanos , Osmio/farmacologia , Células Hep G2 , Proteostase , Antineoplásicos/farmacologia , Apoptose , Linhagem Celular TumoralRESUMO
We report a new osmium(VI) nitrido complex bearing a nonplanar tetradentate ligand with potent anticancer activity. This complex causes mitochondrial damage, which induces liver cancer cell death via oncosis and apoptosis. This is the first osmium-based anticancer candidate that induces oncosis.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Mitocôndrias/efeitos dos fármacos , Nitrilas/farmacologia , Osmio/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Complexos de Coordenação/química , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Mitocôndrias/metabolismo , Estrutura Molecular , Nitrilas/química , Osmio/químicaRESUMO
The osmium(vi) nitrido complex [OsVI(N)(sap)(py)Cl] is a potential anti-cancer drug with promising in vitro antiproliferative activities toward a panel of cancer cell lines, including cisplatin-resistant cells (IC50 values of 2.8-13.8 µM). This drug targets DNA and changes its conformation via covalent binding and insertion. In vitro studies indicate that the drug induces HepG2 cells G2/M phase arrest, disrupts the mitochondrial membrane potential and causes caspase-mediated apoptosis. Further in vivo studies using HepG2-bearing nude mice reveal that this drug not only shows good antitumor efficacy of inhibiting tumor growth, but also does not show the side effect of weight loss.