Synergistic effects of avicins and hydroperoxides on mitochondria: a possible mechanism for the selective killing of cancer cells

Abstract

Avicins D and G are a class of plant saponins with pro-apoptotic activity in cancer cells, which is due in part to the direct perturbation of mitochondria (Haridas et al., PNAS USA, 2001). In this work, we studied the influence of avicins on the energy metabolism in normal rat liver mitochondria. Mitochondria, when treated with avicins, underwent a significant decrease in oxygen consumption in metabolic state 3 and in uncoupled state. The respiration was completely restored by addition of exogenous cytochrome c. Avicins also markedly increased the rotenone-insensitive oxidation of external NADH in the presence of exogenous cytochrome c, without induction of high amplitude swelling of mitochondria, thus confirming that the earlier effect of avicins is due to a permeabilization of the outer mitochondrial membrane to cytochrome c. On the other hand, avicins debilitate the enzymatic NAD(P)H-GSH-dependent antioxidant system of mitochondria due to a decrease of the inner membrane potential generation. As a result, avicins significantly increased a sensitivity of mitochondria to hydroperoxides, causing the acceleration of hydroperoxide-induced oxidation of endogenous NAD(P)H, the inner membrane potential drop and mitochondrial swelling. These data allow to explain relatively high selectivity of avicins in the killing of cancer cells, which have been shown to produce hydroperoxides with a very high rate.