title: 6BIO Enhances Oligonucleotide Activity in Cells: A Potential Combinatorial Anti-androgen Receptor Therapy in Prostate Cancer Cells.
abstract: Approximately 15%-25% of men diagnosed with prostate cancer do not survive their disease. The American Cancer Society estimated that for the year 2016 the number of prostate cancer deaths will be 26,120. Thus, there is a critical need for novel approaches to treat this deadly disease. Using high-throughput small-molecule screening, we found that the small molecule 6-bromo-indirubin-3'-oxime (6BIO) significantly improves the targeting of antisense oligonucleotides (ASOs) delivered by gymnosis (i.e., in the absence of any transfection reagents) in both the cell cytoplasm and the nucleus. Furthermore, as a single agent, 6BIO had the unexpected ability to simultaneously downregulate androgen receptor (AR) expression and AR signaling in prostate cancer cells. This includes downregulating levels of the AR-V7, a drug-resistance-related AR splice variant that is important in the progression of prostate cancer. Combining 6BIO and an anti-AR oligonucleotide (AR-ASO) can augment the downregulation of AR expression. We also demonstrated that 6BIO enhances ASO function and represses AR expression through the inhibition of the two main glycogen synthase kinase 3 (GSK-3) isoforms: GSK-3α and GSK-3β activity. Our findings provide a rationale for the use of 6BIO as a single agent or as part of a combinatorial ASO-based therapy in the treatment of human prostate cancer.
authors.affiliation: Departments of Medical Oncology and Experimental Therapeutics and Molecular and Cellular Biology, City of Hope Medical Center, Duarte, CA 91010, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Medical Oncology and Experimental Therapeutics and Molecular and Cellular Biology, City of Hope Medical Center, Duarte, CA 91010, USA; Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA. Electronic address: dcastanotto@coh.org.
authors.forename: Daniela
authors.initials: D
authors.lastname: Castanotto
authors.affiliation: Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
authors.forename: Sangkil
authors.initials: S
authors.lastname: Nam
authors.affiliation: Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA.
authors.forename: David
authors.initials: D
authors.lastname: Horne
authors.affiliation: Departments of Medical Oncology and Experimental Therapeutics and Molecular and Cellular Biology, City of Hope Medical Center, Duarte, CA 91010, USA; Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA. Electronic address: cstein@coh.org.
authors.forename: Cy
authors.initials: C
authors.lastname: Stein
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003593:Cytoplasm; D004357:Drug Synergism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology*; D009857:Oncogenes / Q000235:genetics; D010091:Oximes / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C483321:6-bromoindirubin-3'-oxime; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D007211:Indoles; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; D010091:Oximes; D011944:Receptors, Androgen; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha
keywords: 6-bromo-indirubin-3′-oxime; AR-V7; ASO; GSK-3α; GSK-3β; LNA; SSO; gymnosis; locked nucleic acid; phosphorothioate