G-quartet oligonucleotides: a new class of signal transducer and activator of transcription 3 inhibitors that suppresses growth of prostate and breast tumors through induction of apoptosis.
Stat3 is a signaling molecular and oncogene activated frequently in many human malignancies including the majority of prostate, breast, and head and neck cancers; yet, no current chemotherapeutic approach has been implemented clinically that specifically targets Stat3. We recently developed G-rich oligodeoxynucleotides, which form intramolecular G-quartet structures (GQ-ODN), as a new class of Stat3 inhibitor. GQ-ODN targeted Stat3 protein directly inhibiting its ability to bind DNA. When delivered into cells using polyethyleneimine as vehicle, GQ-ODN blocked ligand-induced Stat3 activation and Stat3-mediated transcription of antiapoptotic genes. To establish the effectiveness of GQ-ODN as a potential new chemotherapeutic agent, we systemically administered GQ-ODN (T40214 or T40231) plus polyethyleneimine or polyethyleneimine alone (placebo) by tail-vein injection into nude mice with prostate and breast tumor xenografts. Whereas the mean volume of breast tumor xenografts in placebo-treated mice increased >7-fold over 18 days, xenografts in the GQ-ODN-treated mice remained unchanged. Similarly, whereas the mean volume of prostate tumor xenografts in placebo-treated mice increased 9-fold over 10 days, xenografts in GQ-ODN-treated mice increased by only 2-fold. Biochemical examination of tumors from GQ-ODN-treated mice demonstrated a significant reduction in Stat3 activation, levels of the antiapoptotic proteins Bcl-2 and Bcl-xL, and an 8-fold increase in the number of apoptotic cells compared with the tumors of placebo-treated mice. Thus, GQ-ODN targeting Stat3 induces tumor cell apoptosis when delivered into tumor xenografts and represents a novel class of chemotherapeutic agents that holds promise for the systemic treatment of many forms of metastatic cancer.
Jing
Naijie
N
Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA. njing@bcm.tmc.edu
Li
Yidong
Y
Xiong
Weijun
W
Sha
Wei
W
Jing
Ling
L
Tweardy
David J
DJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006151:Guanosine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D010766:Phosphorylation; D011094:Polyethyleneimine / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D050796:STAT3 Transcription Factor; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D006151:Guanosine; D011094:Polyethyleneimine