Toxic effects of copper-based antineoplastic drugs (Casiopeinas) on mitochondrial functions

To elucidate some of the subcellular and biochemical mechanisms of toxicity of metal-based antineoplastic drugs, mitochondria and cells were exposed to Casiopeinas), a new class of copper-based compounds with high antineoplastic activity. The rates of respiration and swelling, the H(+) gradient, and the activities of succinate (SDH) and 2-oxoglutarate dehydrogenases (2-OGDH) and ATPase were measured in mitochondria isolated from rat liver, kidney, heart, and hepatoma AS-30D. Also, oligomycin-sensitive respiration and ATP content in hepatoma AS-30D cells were determined. Casiopeinas) (CS) II-gly and III-i inhibited the rates of state 3 and uncoupled respiration in mitochondria. CS II was 10 times more potent than CS III. The sensitivity to CS II was 4-5-fold higher in mitochondria incubated with 2-OG than with succinate. Thus, at low concentrations (< or =10 nmol (mg protein)(-1); 10 microM), CS II disturbed mitochondrial functions only when 2-OG was present, due to a specific inhibition of 2-OGDH. At high concentrations (> or =15nmol (mg protein)(-1)), CS II-induced stimulation of basal respiration, followed by a strong inhibition, which correlated with K(+)-dependent swelling and cytochrome c release, respectively; K(+)-channel openers induce a similar mitochondrial response. Mitochondria from liver, kidney and hepatoma showed a similar sensitivity towards CS II, whereas heart mitochondria were more resistant. Oxidative phosphorylation and ATP content were also decreased in tumor cells by CS II. The data suggested that CS affected several different mitochondrial sites, bringing about inhibition of respiration and ATP synthesis, which could compromise energy-dependent processes such as cellular duplication.