Background: Drug repurposing is emerging as an attractive strategy with lower attrition rate, lower cost and shorter timeframe than traditional drug discovery methods. Chloroquine (CQ) and its analogs are old drugs originally indicated for malaria treatment. Serendipitous discovery in early years revealed its anti-inflammatory properties, thus allowing its repositioned use in autoimmune diseases. Recent evidence also suggested its potential therapeutic use for anticancer therapy.

Objective: This article reviews the molecular mechanisms, clinical evaluation and recent patents of CQ analogs in cancer therapy.

Methods: Literature and patent searches were conducted using PubMed database and Google Patent/ USPTO Patent Search database, respectively. The keywords including “chloroquine”, “hydroxychloroquine”, “chloroquine analogs”, “chloroquine derivatives”, “repurposing”, “autophagy”, and “cancer” were used.

Results: CQ analogs have been reported to elicit their anticancer effects by modulating autophagy, inducing apoptosis, eliminating cancer stem cells, normalizing tumor vasculature and modulating antitumor immunity. As documented by recent patents and clinical trials, CQ analogs have been repurposed as an adjuvant therapy and combined with other anticancer agents for synergistic enhancement of treatment efficacy. However, most clinical trials on CQ only demonstrated modest improvement in anti-cancer efficacy.

Conclusion: Given that CQ loses its anticancer activity in acidic and hypoxic environment within a tumor, novel CQ analogs and/or their formulations are under active investigation to improve their physicochemical properties and biological activity. On the other hand, identification of new biomarkers for better patient selection has been advocated in future trials in order to realize the repurposing of CQ analogs for cancer treatment in a personalized manner.

背景：与传统药物发现方法相比，药物再利用正在成为一种有吸引力的策略，具有更低的损耗率、更低的成本和更短的时间框架。氯喹 (CQ) 及其类似物是最初用于疟疾治疗的旧药。早年的偶然发现揭示了它的抗炎特性，从而使其重新定位用于自身免疫性疾病。最近的证据还表明其在抗癌治疗中的潜在治疗用途。

目的：本文综述了CQ类似物在癌症治疗中的分子机制、临床评价和近期专利。

方法：文献和专利检索分别使用 PubMed 数据库和 Google Patent/USPTO 专利检索数据库进行。关键词包括“氯喹”、“羟氯喹”、“氯喹类似物”、“氯喹衍生物”、“再利用”、“自噬”和“癌症”。

结果：据报道，CQ 类似物通过调节自噬、诱导细胞凋亡、消除癌症干细胞、使肿瘤脉管系统正常化和调节抗肿瘤免疫来引发其抗癌作用。正如最近的专利和临床试验所证明的那样，CQ 类似物已被重新用作辅助治疗，并与其他抗癌药物联合用于协同增强治疗效果。然而，大多数关于 CQ 的临床试验仅证明了抗癌功效的适度改善。

结论：鉴于 CQ 在肿瘤内的酸性和低氧环境中失去其抗癌活性，新的 CQ 类似物和/或其制剂正在积极研究中，以改善其理化性质和生物活性。另一方面，在未来的试验中提倡识别新的生物标志物以更好地选择患者，以便以个性化的方式实现 CQ 类似物用于癌症治疗的再利用。