Mithramycin, an Agent for Developing New Therapeutic Drugs for Neurodegenerative Diseases

Abstract

Mithramycin A (MTM) has been shown to inhibit cancer growth by blocking the binding of Sp-family transcription factors to gene regulatory elements and is used for the treatment of leukemia and testicular cancer in the United States. In contrast, MTM has also been shown to exert neuroprotective effects in normal cells. An earlier study showed that MTM protected primary cortical neurons against oxidative stress–induced cell death. Recently, we demonstrated that MTM suppressed endoplasmic reticulum (ER) stress–induced neuronal death in organotypic hippocampal slice cultures and cultured hippocampal cells through attenuation of ER stress–associated signal proteins. We also found that MTM decreased neuronal death in area CA1 of the hippocampus after transient global ischemia/reperfusion in mice and restored the ischemia/reperfusion-induced impairment of long-term potentiation in this area. MTM has been shown to prolong the survival of Huntington’s disease model mice and to attenuate dopaminergic neurotoxicity in mice after repeated administration of methamphetamine. In this review, we provide an up to date overview of neuroprotective effects of MTM and less toxic MTM analogs, MTM SK and MTM SDK, on some of the neurodegenerative diseases and discuss the promise of MTM as an agent for developing new therapeutic drugs for such diseases. Keywords:: mithramycin, neuroprotective effect, endoplasmic reticulum stress, Specificity protein 1 (Sp1), neurodegenerative disease