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.