Enhancing or eliminating signals for cell survival to treat disease.

Approximately half of all medical illnesses can be attributed to insufficient or excessive apoptosis. Apoptosis resistance is a cardinal feature of cancer, mediated in many instances, by signal transducer and activator of transcription (STAT) 3. We identified G-quartet oligodeoxynucleotides (GQ-ODNs) as potent and selective inhibitors of Stat3 DNA binding activity in vitro. We report here that GQ-ODNs are capable of inhibiting the growth of nude mouse xenografts of breast and prostate tumors. We developed a rat model of severe hemorrhagic shock (HS) to assess the benefits of promoting Stat3 activity in diseases marked by excessive apoptosis. Administration of the Stat3-activating cytokine IL-6 at the initiation of resuscitation from HS activated intra-cardiac Stat3, reversed cardiac apoptosis, left ventricular dysfunction and hypovolemic circulatory collapse (HCC) and resulted in a 5-fold reduction in mortality; pre-treatment of rats with GQ-ODN prevented the reversal of cardiac apoptosis and HCC by IL-6. Thus, targeting of Stat3 may be a useful for treatment of multiple cancers; agents that activate Stat3 may be beneficial in acute insults that cause apoptosis in organs critical for survival.