T40214/PEI complex: a potent therapeutics for prostate cancer that targets STAT3 signaling.
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-bearing nude mice due to that T40214 inhibited STAT3 activation and then greatly promoted apoptosis, reduced angiogenesis and cell proliferation in prostate tumors.


CONCLUSIONS
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.
Weerasinghe
Priya
P
Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Li
Yifei
Y
Guan
Yongli
Y
Zhang
Ruiwen
R
Tweardy
David J
DJ
Jing
Naijie
N
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology / Q000627:therapeutic use*; D011094:Polyethyleneimine; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
C510005:GQ-ODN T40214; D009838:Oligodeoxyribonucleotides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D011094:Polyethyleneimine