Copper(II) thiosemicarbazonate molecular modifications modulate apoptotic and oxidative effects on U937 cell line.
To improve the solubility in aqueous media of bis(citronellalthiosemicarbazonato)copper(II) [Cu(S-tcitr)(2)], a compound that is effective in inhibiting cell growth of U937 cell line, the ligand was modified adding an ethylmorpholine group. [Cu(S-tcitr)(2)] and [Cu(Etmorph-S-tcitr)(2)] cytotoxic effects are compared using as a model U937 cells. [Cu(Etmorph-S-tcitr)(2)] results more effective in cell growth inhibition (IC(50:) 2.3 vs 14.8 μM). Apoptosis in [Cu(Etmorph-S-tcitr)(2)] treated cells was apparent after 8h, with increased caspase activities, and these effects were not observed for [Cu(S-tcitr)(2)]. During the exposure to [Cu(Etmorph-S-tcitr)(2)], ROS (reactive oxygen species) and TBARS (Thiobarbituric acid reactive substances) significantly increased, coupled with reduced glutathione (GSH) levels and significant activation of superoxide dismutase (SOD). These intracellular scavengers seem to limit the early ROS and TBARS increases in U937 cells exposed to [Cu(S-tcitr)(2)]. Both complexes interacted in vitro with naked DNA: UV-visible and CD titration reveal that they can induce DNA structure modifications in a distinct way. Furthermore, the complexes induced DNA damage on U937 cells at concentrations higher than IC(50). The mechanisms of action and the effects of these two complexes are remarkably different even though they have the same coordination geometry around copper(II) and differ only for the presence of the ethylmorpholine group.
Dep. of General and Inorganic Chemistry, Analytical Chemistry, Physical Chemistry University of Parma, Parco Area delle Scienze 17/a 43124 Parma, Italy.
Franco
F
Bisceglie
Silvana
S
Pinelli
Rossella
R
Alinovi
Pieralberto
P
Tarasconi
Annamaria
A
Buschini
Francesca
F
Mussi
Antonio
A
Mutti
Giorgio
G
Pelosi
D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry*; D004249:DNA Damage; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D013056:Spectrophotometry, Ultraviolet; D013482:Superoxide Dismutase / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D020298:U937 Cells
D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D013882:Thiosemicarbazones; D003300:Copper; D013482:Superoxide Dismutase