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

• Published in: Cancer research (Chicago, Ill.) Vol. 64; no. 18; pp. 6603 - 6609
• Main Authors: NAIJIE JING, YIDONG LI, WEIJUN XIONG, WEI SHA, LING JING, TWEARDY, David J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.09.2004
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - genetics; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Division - drug effects; Cell Division - genetics; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Guanosine - chemistry; Guanosine - genetics; Humans; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Oligonucleotides - chemistry; Oligonucleotides - genetics; Oligonucleotides - pharmacology; Pharmacology. Drug treatments; Phosphorylation; Polyethyleneimine - pharmacology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; STAT3 Transcription Factor; Structure-Activity Relationship; Substrate Specificity; Trans-Activators - antagonists & inhibitors; Trans-Activators - genetics; Trans-Activators - metabolism; Tumors; Xenograft Model Antitumor Assays; Growth inhibitor; Signal transduction; Signal; Transcription; Activator; Cell death; Oligonucleotide; Mammary gland; Urogenital system; Prostate; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-03-4041

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.