Shah Esha T, Upadhyaya Akanksha, Philp Lisa K, Tang Tiffany, Skalamera Dubravka, Gunter Jennifer, Nelson Colleen C, Williams Elizabeth D, Hollier Brett G
Australian Prostate Cancer Research Centre-Queensland, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Australia.
Translational Research Institute, Brisbane, Australia.
Clin Exp Metastasis. 2016 Apr;33(4):385-99. doi: 10.1007/s10585-016-9785-y. Epub 2016 Mar 1.
The majority of prostate cancer (PCa) deaths occur due to the metastatic spread of tumor cells to distant organs. Currently, there is a lack of effective therapies once tumor cells have spread outside the prostate. It is therefore imperative to rapidly develop therapeutics to inhibit the metastatic spread of tumor cells. Gain of cell motility and invasive properties is the first step of metastasis and by inhibiting motility one can potentially inhibit metastasis. Using the drug repositioning strategy, we developed a cell-based multi-parameter primary screening assay to identify drugs that inhibit the migratory and invasive properties of metastatic PC-3 PCa cells. Following the completion of the primary screening assay, 33 drugs were identified from an FDA approved drug library that either inhibited migration or were cytotoxic to the PC-3 cells. Based on the data obtained from the subsequent validation studies, mitoxantrone hydrochloride, simvastatin, fluvastatin and vandetanib were identified as strong candidates that can inhibit both the migration and invasion of PC-3 cells without significantly affecting cell viability. By employing the drug repositioning strategy instead of a de novo drug discovery and development strategy, the identified drug candidates have the potential to be rapidly translated into the clinic for the management of men with aggressive forms of PCa.
大多数前列腺癌（PCa）死亡是由于肿瘤细胞转移扩散到远处器官所致。目前，一旦肿瘤细胞扩散到前列腺以外，就缺乏有效的治疗方法。因此，迫切需要迅速开发抑制肿瘤细胞转移扩散的治疗方法。细胞运动性和侵袭性的增强是转移的第一步，通过抑制运动性有可能抑制转移。利用药物重新定位策略，我们开发了一种基于细胞的多参数初步筛选试验，以鉴定抑制转移性PC-3前列腺癌细胞迁移和侵袭特性的药物。在初步筛选试验完成后，从美国食品药品监督管理局（FDA）批准的药物库中鉴定出33种药物，这些药物要么抑制迁移，要么对PC-3细胞具有细胞毒性。根据后续验证研究获得的数据，盐酸米托蒽醌、辛伐他汀、氟伐他汀和凡德他尼被确定为强有力的候选药物，它们可以抑制PC-3细胞的迁移和侵袭，而不会显著影响细胞活力。通过采用药物重新定位策略而非全新的药物发现和开发策略，所鉴定的候选药物有可能迅速转化为临床应用，用于治疗侵袭性前列腺癌男性患者。
