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.
Molecular therapy : the journal of the American Society of Gene Therapy. 2017 Jan 04 [Epub]
Xiaowei Zhang, Daniela Castanotto, Sangkil Nam, David Horne, Cy Stein
Departments of Medical Oncology and Experimental Therapeutics and Molecular and Cellular Biology, City of Hope Medical Center, Duarte, CA 91010, USA., 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: ., Beckman Research Institute, City of Hope Medical Center, Duarte, CA 91010, USA., 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: .