Targeting signal transducer and activator of transcription 3 with G-quartet oligonucleotides: a potential novel therapy for head and neck cancer

Abstract

Signal transducer and activator of transcription 3 (Stat3) is a critical mediator of oncogenic signaling activated frequently in many types of human cancer where it contributes to tumor cell growth and resistance to apoptosis. Stat3 has been proposed as a promising target for anticancer drug discovery. Recently, we developed a series of G-quartet oligodeoxynucleotides (GQ-ODN) as novel and potent Stat3 inhibitors, which significantly suppressed the growth of prostate and breast tumors in nude mice. In the present study, we showed that GQ-ODN specifically inhibited DNA-binding activity of Stat3 as opposed to Stat1. Computer-based docking analysis revealed that GQ-ODN predominantly interacts with the SH2 domains of Stat3 homodimers to destabilize dimer formation and disrupt DNA-binding activity. We employed five regimens in the treatment of nude mice with tumors of head and neck squamous cell carcinoma (HNSCC): placebo, paclitaxel, GQ-ODN T40214, GQ-ODN T40231, and T40214 plus paclitaxel. The mean size of HNSCC tumors over 21 days only increased by 1.7-fold in T40214-treated mice and actually decreased by 35% in T40214 plus paclitaxel -treated mice whereas the mean size of HNSCC tumors increased 9.4-fold in placebotreated mice in the same period. These findings show that GQ-ODN has potent activity against HNSCC tumor xenografts alone and in combination with paclitaxel. [Mol Cancer Ther 2006;5(2):279 -86]

Evidence That G-quadruplex DNA Accumulates in the Cytoplasm and Participates in Stress Granule Assembly in Response to Oxidative Stress

“…G4DNA has been proposed as a drug target for treatment of cancer and other diseases (74). Our work here expands the rationale for targeting G4DNA and provides further support for G4DNA mimics as potential drugs (67,68).…”

“…Several laboratories have reported that many cell types, usually cancer cells, spontaneously take up exogenous G4DNA (67)(68)(69)(70). G4DNA taken up by cells causes various biological responses including apoptosis in tumor cells (69, 71).…”

Cucurbitacin I Suppressed Stem-Like Property and Enhanced Radiation-Induced Apoptosis in Head and Neck Squamous Carcinoma–Derived CD44+ALDH1+ Cells

“…Targeting STAT3 signaling by introducing dominant-negative constructs, decoy oligonucleotides, or antisense oligonucleotides to HNSCC cells significantly inhibits growth and induces apoptosis (26). Because persistent activation of STAT3 promotes tumor cell proliferation and survival, further contributing to tumor progression and migration, abrogation of STAT3 signaling is emerging as a potential cancer therapy strategy.…”

STAT3 gene polymorphisms and susceptibility to non-small cell lung cancer

“…Constitutively activated STAT3 activity has been routinely observed in multiple human cancers including lung, gastric, skin, head and neck, ovarian, breast, colon, and prostate (Bromberg et al, 1999;Bowman et al, 2000;Yu and Jove, 2004;Hsieh et al, 2005;Lin et al, 2005;Yin et al, 2006;Sansone et al, 2007;Abdulghani et al, 2008). In vitro and animal models have shown that inactivation of STAT3 inhibited carcinogenesis and the growth of established tumors, while enhancing expression of this gene promoted tumor incidence and growth (Yu and Jove, 2004;Jing et al, 2006;Siddiquee et al, 2007a,b;Weerasinghe et al, 2007;Bollrath et al, 2009). Moreover, activation of STAT3 has been associated with advanced stages of prostate cancer (Horinaga et al, 2005) and metastatic progression of several different cancer types, including lung cancer (Dauer et al, 2005).…”