Universite de Tours, EA7501 GICC, Tours, France.
Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Curr Med Chem. 2021;28(11):2218-2233. doi: 10.2174/0929867327666200908114411.
Drug repurposing has lately received increasing interest in several diseases especially in cancers, due to its advantages in facilitating the development of new therapeutic strategies, by adopting a cost-friendly approach and avoiding the strict Food and Drug Administration (FDA) regulations. Acriflavine (ACF) is an FDA approved molecule that has been extensively studied since 1912 with antiseptic, trypanocidal, anti-viral, anti-bacterial and anti-cancer effects. ACF has been shown to block the growth of solid and hematopoietic tumor cells. Indeed, ACF acts as an inhibitor of various proteins, including DNA-dependent protein kinases C (DNA-PKcs), topoisomerase I and II, hypoxia-inducible factor 1α (HIF-1α), in addition to its recent discovery as an inhibitor of the signal transducer and activator of transcription (STAT). Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expression of the constitutively active tyrosine kinase BCR-ABL. This protein allows the activation of several signaling pathways known for their role in cell proliferation and survival, such as the JAK/STAT pathway. CML therapy, based on tyrosine kinase inhibitors (TKIs), such as imatinib (IM), is highly effective. However, 15% of patients are refractory to IM, where in some cases, 20-30% of patients become resistant. Thus, we suggest the repurposing of ACF in CML after IM failure or in combination with IM to improve the anti-tumor effects of IM. In this review, we present the different pharmacological properties of ACF along with its anti-leukemic effects in the hope of its repurposing in CML therapy.
药物重定位最近在多种疾病中引起了越来越多的关注，尤其是癌症，因为它在促进新的治疗策略的发展方面具有优势，采用了经济实惠的方法，并且避免了严格的美国食品和药物管理局（FDA）规定。吖啶黄素（ACF）是一种获得 FDA 批准的分子，自 1912 年以来，它一直被广泛研究，具有防腐、杀锥虫、抗病毒、抗菌和抗癌作用。ACF 已被证明能阻止实体瘤和造血肿瘤细胞的生长。事实上，ACF 作为多种蛋白质的抑制剂，包括 DNA 依赖性蛋白激酶 C（DNA-PKcs）、拓扑异构酶 I 和 II、缺氧诱导因子 1α（HIF-1α），以及最近发现其作为信号转导和转录激活剂（STAT）的抑制剂。慢性髓性白血病（CML）是一种克隆性骨髓增生性疾病，其特征是表达组成性激活的酪氨酸激酶 BCR-ABL。这种蛋白质允许几种信号通路的激活，这些信号通路因其在细胞增殖和存活中的作用而闻名，如 JAK/STAT 通路。以酪氨酸激酶抑制剂（TKIs）为基础的 CML 治疗，如伊马替尼（IM），非常有效。然而，15%的患者对 IM 有抗药性，在某些情况下，20-30%的患者会产生抗药性。因此，我们建议在 IM 失败后或与 IM 联合使用 ACF 对 CML 进行重新定位，以提高 IM 的抗肿瘤作用。在这篇综述中，我们介绍了 ACF 的不同药理学特性及其在白血病中的抗白血病作用，希望能将其重新应用于 CML 的治疗中。
