Normandie Univ, UNICAEN, INSERM U1086 ANTICIPE (Interdisciplinary Research Unit for Cancers Prevention and Treatment), BioTICLA axis (Biology and Innovative Therapeutics for Ovarian Cancers), 14000 Caen, France.
UNICANCER, Comprehensive Cancer Center François Baclesse, 14000 Caen, France.
Int J Mol Sci. 2020 Jul 27;21(15):5339. doi: 10.3390/ijms21155339.
Failure of conventional treatments is often observed in cancer management and this requires the development of alternative therapeutic strategies. However, new drug development is known to be a high-failure process because of the possibility of a lower efficacy than expected for the drug or appearance of non-manageable side effects. Another way to find alternative therapeutic drugs consists in identifying new applications for drugs already approved for a particular disease: a concept named "drug repurposing". In this context, several studies demonstrated the potential anti-tumour activity exerted by α1-adrenergic receptor antagonists and notably renewed interest for naftopidil as an anti-cancer drug. Naftopidil is used for benign prostatic hyperplasia management in Japan and a retrospective study brought out a reduced incidence of prostate cancer in patients that had been prescribed this drug. Further studies showed that naftopidil exerted anti-proliferative and cytotoxic effects on prostate cancer as well as several other cancer types in vitro, as well as ex vivo and in vivo. Moreover, naftopidil was demonstrated to modulate the expression of Bcl-2 family pro-apoptotic members which could be used to sensitise cancer cells to targeting therapies and to overcome resistance of cancer cells to apoptosis. For most of these anti-cancer effects, the molecular pathway is either not fully deciphered or shown to involve α1-adrenergic receptor-independent pathway, suggesting off target transduction signals. In order to improve its efficacy, naftopidil analogues were designed and shown to be effective in several studies. Thereby, naftopidil appears to display anti-cancer properties on different cancer types and could be considered as a candidate for drug repurposing although its anti-cancerous activities need to be studied more deeply in prospective randomized clinical trials.
在癌症治疗中，经常观察到常规治疗的失败，这就需要开发替代的治疗策略。然而，新药物的开发被认为是一个高失败率的过程，因为药物的疗效可能低于预期，或者出现不可控制的副作用。另一种寻找替代治疗药物的方法是确定已经批准用于特定疾病的药物的新用途：这一概念被称为“药物再利用”。在这方面，几项研究表明，α1-肾上腺素能受体拮抗剂具有潜在的抗肿瘤活性，特别是萘哌地尔作为一种抗癌药物重新引起了人们的兴趣。萘哌地尔在日本用于治疗良性前列腺增生，一项回顾性研究表明，服用该药的患者前列腺癌的发病率降低。进一步的研究表明，萘哌地尔在体外、离体和体内对前列腺癌和其他几种癌症类型具有抗增殖和细胞毒性作用。此外，萘哌地尔被证明可以调节 Bcl-2 家族促凋亡成员的表达，这可以用来使癌细胞对靶向治疗敏感，并克服癌细胞对凋亡的抵抗。对于大多数这些抗癌作用，其分子途径要么尚未完全阐明，要么显示涉及α1-肾上腺素能受体非依赖性途径，提示存在非靶向转导信号。为了提高其疗效，设计了萘哌地尔类似物，并在几项研究中证明是有效的。因此，萘哌地尔似乎对不同类型的癌症具有抗癌特性，可以被认为是药物再利用的候选药物，尽管其抗癌活性需要在前瞻性随机临床试验中更深入地研究。
