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In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids(Mito HCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH? àand ROO? àinduced lipid peroxidation. H_2O_2 production was decreased significantly by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines(HepG2, L02 and WI38) indicated that the Mito HCAs were selective for cancer cells. Interestingly, the Mito HCAs both with or without Ca~(2+)triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore(m PTP), cyclosporin A, attenuated mitochondrial damage and cell apoptosis, indicating that m PTP may be involved in the antiproliferative activity of Mito HCAs.Further studies focused on structural optimization of these compounds are onging.
In order to develop agents with superior chemopreventive and chemotherapeutic properties against hepatocellular carcinomas, mitochondria-targeted hydroxycinnamic acids (Mito HCAs) were synthesized by conjugation with a triphenylphosphonium cation. These synthetic compounds were evaluated for their antioxidant activities in hepatic mitochondria, including against OH? àand ROO® àinduced lipid peroxidation. H_2O_2 production was markedly increased by increasing glutathione peroxidase and catalase activities. In addition, cell proliferation data from three cell lines (HepG2, L02 and WI38) indicated that the Mito HCAs were selective for cancer cells. Interestingly, the Mito HCAs both with or without Ca ~ (2+) triggered mitochondrial dysfunction by inducing mitochondrial swelling, collapsing the mitochondrial membrane potential and causing cytochrome c release. In particular, an inhibitor of the mitochondrial permeability transition pore (m PTP), cyclosporin A , attenuated mitochondrial dama ge and cell apoptosis, indicating that m PTP may be involved in the antiproliferative activity of Mito HCAs. Future studies focused on structural optimization of these compounds are onging.