Inhibition of Stat3 activation and tumor growth suppression of non-small cell lung cancer by G-quartet oligonucleotides.
Lung cancer is the leading cause of cancer mortality in the United States. Despite advances made over the past decades, the overall survival of patients with lung cancer remains dismal. Here we report novel G-quartet oligodeoxynucleotides (GQ-ODN) that were designed to selectively target signal transducer and activator of transcription 3 (Stat3), in the treatment of human non-small cell lung cancer (NSCLC). The objective of this study was to evaluate the effects of two novel GQ-ODN STAT3 inhibitors, T40214 and T40231, on NSCLC bearing nude mice. NSCLC bearing nude mice were assigned to 5 groups, which were treated by vehicle, control ODN, T40214, T40231, and Paclitaxel, respectively. Tumors were measured, isolated and analyzed using Western blotting, immuno-histochemistry, RPA and TUNEL. Results show that GQ-ODN T40214 and T40231 significantly suppress the growth of NSCLC tumors in nude mice by selectively inhibiting the activation of Stat3 and its downstream proteins Bcl-2, Bcl-xL, Mcl-1, survivin, VEGF, Cyclin D1 and c-myc; thereby, promoting apoptosis and reducing angiogenesis and cell proliferation. These findings validate Stat3 as an important molecular target for NSCLC therapy and demonstrate the efficacy of GQ-ODN in inhibiting Stat3 phosphorylation.
Weerasinghe
Priya
P
Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.
Garcia
Gabriela E
GE
Zhu
Qiqing
Q
Yuan
Ping
P
Feng
Lili
L
Mao
Li
L
Jing
Naijie
N
D000818:Animals; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D007150:Immunohistochemistry; D051034:Inhibitor of Apoptosis Proteins; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D017239:Paclitaxel / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D011487:Protein Conformation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D051020:bcl-X Protein / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism
C107489:BIRC5 protein, human; C510005:GQ-ODN T40214; C510006:GQ-ODN T40231; D051034:Inhibitor of Apoptosis Proteins; C489427:MYC protein, human; C579094:Mcl1 protein, mouse; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D009838:Oligodeoxyribonucleotides; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D050796:STAT3 Transcription Factor; D000077022:Survivin; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D019938:Cyclin D1; D017239:Paclitaxel