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.
Tweardy
David J
DJ
Section of Infectious Diseases, Department of Medicine and The Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. dtweardy@bcm.edu
Jing
Naijie
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012769:Shock / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
D015850:Interleukin-6; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse