Turanli Beste, Grøtli Morten, Boren Jan, Nielsen Jens, Uhlen Mathias, Arga Kazim Y, Mardinoglu Adil
Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
Department of Bioengineering, Istanbul Medeniyet University, Istanbul, Turkey.
Front Physiol. 2018 May 15;9:500. doi: 10.3389/fphys.2018.00500. eCollection 2018.
Drug repositioning has gained attention from both academia and pharmaceutical companies as an auxiliary process to conventional drug discovery. Chemotherapeutic agents have notorious adverse effects that drastically reduce the life quality of cancer patients so drug repositioning is a promising strategy to identify non-cancer drugs which have anti-cancer activity as well as tolerable adverse effects for human health. There are various strategies for discovery and validation of repurposed drugs. In this review, 25 repurposed drug candidates are presented as result of different strategies, 15 of which are already under clinical investigation for treatment of prostate cancer (PCa). To date, zoledronic acid is the only repurposed, clinically used, and approved non-cancer drug for PCa. Anti-cancer activities of existing drugs presented in this review cover diverse and also known mechanisms such as inhibition of mTOR and VEGFR2 signaling, inhibition of PI3K/Akt signaling, COX and selective COX-2 inhibition, NF-κB inhibition, Wnt/β-Catenin pathway inhibition, DNMT1 inhibition, and GSK-3β inhibition. In addition to monotherapy option, combination therapy with current anti-cancer drugs may also increase drug efficacy and reduce adverse effects. Thus, drug repositioning may become a key approach for drug discovery in terms of time- and cost-efficiency comparing to conventional drug discovery and development process.
药物重新定位作为传统药物研发的辅助过程，已受到学术界和制药公司的关注。化疗药物具有臭名昭著的副作用，会大幅降低癌症患者的生活质量，因此药物重新定位是一种很有前景的策略，可用于识别具有抗癌活性且对人体健康副作用可耐受的非癌症药物。有多种用于发现和验证重新利用药物的策略。在本综述中，介绍了25种通过不同策略得到的重新利用药物候选物，其中15种已在进行治疗前列腺癌（PCa）的临床研究。迄今为止，唑来膦酸是唯一一种重新利用的、临床使用且已获批用于PCa的非癌症药物。本综述中介绍的现有药物的抗癌活性涵盖多种已知机制，如抑制mTOR和VEGFR2信号传导、抑制PI3K/Akt信号传导、COX和选择性COX-2抑制、NF-κB抑制、Wnt/β-连环蛋白途径抑制、DNMT1抑制和GSK-3β抑制。除了单一疗法选项外，与当前抗癌药物联合治疗也可能提高药物疗效并减少副作用。因此，与传统药物研发过程相比，就时间和成本效益而言，药物重新定位可能成为药物研发的关键方法。
