Novel antitumor agent adaphostin
Lipophilic, adamantyl ester of tyrphostin AG 957 induces Bcr/abl down-regulation. Causes intracellular peroxide production followed by DNA strand breaks. Adaphostin shows significant and selective activity against chronic myeloid leukemia and acute myeloid leukemia. Scientists are studying adaphostin as a potential anticancer drug. Generates reactive oxygen species. This plays a critical role in the cytotoxicity of this agent. Adaphostin induced superoxide and apoptosis in a dose-dependent and time-dependent fashion in both Ph-positive and Ph-negative cells. Scientists speculate a good antileukemic strategy might combine adaphostin with proteasome inhibitors and thereby potentiating oxidative damage. Virginia Commonwealth University researchers tried cotreatment of Jurkat cells with slightly toxic concentrations of adaphostin and proteasome inhibitors. This apparently potentiated mitochondrial damage (cytochrome c release), caspase activation, and apoptosis. Adaphostin induces superoxide and apoptosis in a dose-dependent and time-dependent fashion in both Ph-positive and Ph-negative cells. NCI researchers found adaphostin treatment induced a decrease in the phosphorylation of nucleophosmin. Proteomic analysis identifies oxidative stress induction by adaphostin
|