Sequence-selective DNA binding drugs mithramycin A and chromomycin A(3) are potent inhibitors of neuronal apoptosis induced by oxidative stress and DNA damage in cortical neurons

Global inhibitors of RNA or protein synthesis such as actinomycin D or cycl oheximide abrogate neuronal apoptosis induced by numerous pathological stim uli in vitro and in vivo. The clinical application of actinomycin D or cycl oheximide to human neurological disease has been limited by the toxicities of these agents. To overcome these toxicities, strategies must be developed to inhibit selectively the expression of deleterious proapoptotic proteins , while leaving the expression of antiapoptotic, proregeneration, and other critical homeostatic proteins unperturbed. Mithramycin A (trade name Plica mycin) is an aureolic acid antibiotic that has been used in humans to treat hypercalcemia and several types of cancers. This class of agents is believ ed to act, in part, by selectively inhibiting gene expression by displacing transcriptional activators that bind to G-C-rich regions of promoters. Her e we demonstrate that mithramycin A and its structural analog chromomycin A 3 are potent inhibitors of neuronal apopotosis induced by glutathione deple tion-induced oxidative stress of the DNA-damaging agent camptothecin. We co rrelate the protective effects of mithramycin A with its ability to inhibit enhanced DNA binding of the transcription factors Sp1 andSp3 to their cogn ate "G-C" box induced by oxidative stress or DNA damage. The protective eff ects of mithramycin A cannot be attributed to global inhibition of protein synthesis. Together, these results suggest that mithramycin A and its struc tural analogs may be effective agents for the treatment of neurological dis eases associated with aberrant activation of apoptosis and highlight the po tential use of sequence-selective DNA-binding drugs as neurological therape utics.