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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.

Abstract
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.
AuthorsNaijie Jing, Yidong Li, Weijun Xiong, Wei Sha, Ling Jing, David J Tweardy
JournalCancer research (Cancer Res) Vol. 64 Issue 18 Pg. 6603-9 (Sep 15 2004) ISSN: 0008-5472 [Print] United States
PMID15374974 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • DNA-Binding Proteins
  • Oligonucleotides
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators
  • Guanosine
  • Polyethyleneimine
Topics
  • Animals
  • Apoptosis (drug effects, genetics)
  • Breast Neoplasms (drug therapy, genetics, pathology)
  • Cell Division (drug effects, genetics)
  • DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
  • Female
  • Guanosine (chemistry, genetics)
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Models, Molecular
  • Oligonucleotides (chemistry, genetics, pharmacology)
  • Phosphorylation
  • Polyethyleneimine (pharmacology)
  • Prostatic Neoplasms (drug therapy, genetics, pathology)
  • STAT3 Transcription Factor
  • Structure-Activity Relationship
  • Substrate Specificity
  • Trans-Activators (antagonists & inhibitors, genetics, metabolism)
  • Xenograft Model Antitumor Assays

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