T40214/PEI complex: A potent therapeutics for prostate cancer that targets STAT3 signaling.

The Prostate 2008 Jul 9; In press

Weerasinghe P P, Li Y Y, Guan Y Y, Zhang R R, Tweardy D DJ, Jing N N

Department of Medicine, Baylor College of Medicine, Houston, Texas.

BACKGROUND: Prostate cancer (PC) is the most common cancer among men in American and the second leading cause of cancer death. The treatment options employed for patients with advanced and metastatic PC are limited. As a critical mediator of oncogenic signaling, STAT3 is active in 82% of patients with PC. STAT3 has become a very important molecular target for PC therapy since it upregulates the oncogenes encoding apoptosis inhibitors, cell cycle regulators, and inducers of angiogenesis. However, no anti-tumor drug whose primary mode of action is to target STAT3 has yet reached the clinic. To this end, we have laid the initial groundwork to develop the STAT3-inhibiting G-quartet oligodeoxynucleotide (GQ-ODN), T40214, for treatment of PCs. METHODS: We employed in vitro and in vivo assays, including Western blots, EMSA, cell cycle analysis, TUNEL and xenograft models, to determine the drug efficacy and mechanism of T40214/PEI complex. RESULTS: The results demonstrated that (i) T40214 significantly inhibited STAT3 activation and induced apoptosis in both androgen-dependent and androgen-independent PC cells; (ii) T40214 delivered by ployethylenimine (PEI) significantly suppressed prostate tumor growth in tumor-bearning nude mice due to that T40214 inhibited STAT3 activation and then greatly promoted apoptosis, reduced angiogenesis and cell proliferation in prostate tumors. CONCLUSION: Our studies suggested that STAT3 is a critical oncogenic signal, which strongly influences the progression of PCs and that T40214/PEI complex is a promising candidate for treatment of patients with prostate tumors and represents a novel strategy for PC therapy. Prostate (c) 2008 Wiley-Liss, Inc.

Keywords: prostate cancer STAT3