Zhang Xiaowei, Castanotto Daniela, Nam Sangkil, Horne David, Stein Cy
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.
Mol Ther. 2017 Jan 4;25(1):79-91. doi: 10.1016/j.ymthe.2016.10.017.
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.
约15%-25%被诊断患有前列腺癌的男性无法从该疾病中存活下来。美国癌症协会估计，2016年前列腺癌死亡人数将达到26,120人。因此，迫切需要新的方法来治疗这种致命疾病。通过高通量小分子筛选，我们发现小分子6-溴靛玉红-3'-肟（6BIO）能显著提高通过裸转（即在没有任何转染试剂的情况下）递送的反义寡核苷酸（ASO）在细胞质和细胞核中的靶向性。此外，作为单一药物，6BIO具有意想不到的能力，能够同时下调前列腺癌细胞中的雄激素受体（AR）表达和AR信号传导。这包括下调AR-V7的水平，AR-V7是一种与耐药相关的AR剪接变体，在前列腺癌进展中起重要作用。将6BIO与抗AR寡核苷酸（AR-ASO）联合使用可增强AR表达的下调作用。我们还证明，6BIO通过抑制两种主要的糖原合酶激酶3（GSK-3）亚型：GSK-3α和GSK-3β的活性来增强ASO功能并抑制AR表达。我们的研究结果为将6BIO作为单一药物或作为基于ASO的联合治疗的一部分用于治疗人类前列腺癌提供了理论依据。
