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Survival of tumor cells is favoured by mitochondrial changes that make death induction\udmore difficult in a variety of stress conditions, such as exposure to chemotherapeutics. These\udchanges are not fully characterized in tumor mitochondria, and include unbalance of the redox\udequilibrium, inhibition of permeability transition pore (PTP) opening through kinase signalling\udpathways and modulation of members of the Bcl-2 protein family. Here we show that a novel\udchemotherapeutic, the Gold(III)-dithiocarbamato complex AUL12, induces oxidative stress and\udtumor cell death both favouring PTP opening and activating the pro-apoptotic protein Bax of the\udBcl-2 family. AUL12 inhibits the respiratory complex I and causes a rapid burst of mitochondrial\udsuperoxide levels, leading to activation of the mitochondrial fraction of GSK-3α/β and to the\udensuing phosphorylation of the mitochondrial chaperone cyclophilin D, which in turn facilitates\udPTP opening. In addition, following AUL12 treatment Bax interacts with GSK-3α/β and\udtranslocates onto mitochondria, where it contributes to PTP induction and tumor cell death. These\udfindings provide evidence that targeting the redox equilibrium maintained by mitochondria in tumor\udcells allow to hit crucial mechanisms that shield neoplasms from the toxicity of many anti-tumor\udstrategies, and identify AUL12 as a promising chemotherapeutic compound

cell death and disease

Chemotherapeutic induction of mitochondrial oxidative stress activates GSK-3α/β and Bax, leading to permeability transition pore opening and tumor cell death