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.
Section of Infectious Diseases, Department of Medicine and The Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. dtweardy@bcm.edu
David J
DJ
Tweardy
Naijie
N
Jing
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