Hydroxylamido-amino acid complexes of oxovanadium(V). Toxicological study in cell culture and in a zebrafish model.
Oxovanadium(V) complexes [VO(NH(2)O)(2)(val)] and [VO(NH(2)O)(2)(met)] caused inhibition of cell proliferation in two osteoblast cell lines, MC3T3-E1 and UMR106, as well as the viability of zebrafish eggs. In MC3T3-E1, both compounds inhibited cell proliferation (up to ca. 40% at 25 μM [VO(NH(2)O)(2)(val)] and 25% at 25 μM [VO(NH(2)O)(2)(met)]). This effect occurs in a dose response manner from 2.5 μM (p < 0.01) with a more deleterious action of [VO(NH(2)O)(2)(met)]. In UMR106 tumoral cells, [VO(NH(2)O)(2)(val)] inhibited cell proliferation up to 75% from 25 μM while [VO(NH(2)O)(2)(met)] behaved as an inhibitory agent in the whole range of concentrations (p < 0.01). Similar toxic effects were obtained from morphological studies in cell cultures. Moreover, the IC(50) values for both complexes in culture studies correlated with the IC(50) values obtained with an in vivo model of toxicity (FET test). Besides, the cytotoxicity evaluation in cell culture showed a decrease in mitochondrial activity which was stronger for [VO(NH(2)O)(2)(met)] than for [VO(NH(2)O)(2)(val)] (44% vs. 58% at 25 μM) in both cell lines (p < 0.001). Genotoxicity assessed by micronuclei induction also showed a stronger effect of [VO(NH(2)O)(2)(met)] in both cell lines. Besides, [VO(NH(2)O)(2)(val)] caused DNA damage determined by comet formation in MC3T3-E1 cells in the range of 2.5-25 μM, while this effect could not be observed in the osteosarcoma cells. On the other hand, [VO(NH(2)O)(2)(val)] enhanced ROS levels over basal up to 225% and 170% at 100 μM in MC3T3-E1 and UMR106 cells, respectively (p < 0.01). For [VO(NH(2)O)(2)(met)] a similar situation was observed, suggesting an important role for oxidative stress in the toxicity mechanism of action. Although both complexes showed interesting results that would deserve further drug development [VO(NH(2)O)(2)(val)] was more stable than [VO(NH(2)O)(2)(met)] in the solid state. Therefore, we consider that [VO(NH(2)O)(2)(val)] is a good candidate to be tested in in vivo models as a potential antitumoral agent.
Cátedra de Bioquímica Patológica and CEQUINOR, Facultad Ciencias Exactas, Universidad Nacional de La Plata, 47 y 115 (1900) La Plata, Argentina.
Ignacio E
IE
León
Ana L
AL
Di Virgilio
Daniel A
DA
Barrio
Gabriel
G
Arrambide
Dinorah
D
Gambino
Susana B
SB
Etcheverry
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004355:Drug Stability; D005260:Female; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010063:Ovum / Q000187:drug effects / Q000254:growth & development; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D014638:Vanadates / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D015027:Zebrafish
D000970:Antineoplastic Agents; D014638:Vanadates