常见的抗疟药如青蒿素、氯喹及其衍生物也具有有效的抗炎、抗病毒和抗癌特性。在寻找治疗难治性胰腺癌的新疗法的过程中，我们发现4-氨基喹啉衍生物具有显着的抗疟原虫特性和良好的体内安全性，对胰腺导管腺癌（PDAC）具有显着的抗癌活性和相当大的疗效在体内异种移植模型中。本研究的目的是以药物再利用的方式进一步研究这些化合物的抗癌特性。这些化合物在 2D 培养细胞（体外）和斑马鱼 PDAC 异种移植模型（体内）中在纳摩尔至低微摩尔浓度下显示出深远的细胞毒性作用。对其细胞毒性作用机制的更深入了解表明，这些化合物可诱导细胞凋亡，同时增加活性氧水平并抑制自噬。对自噬调节的进一步研究证明，测试的喹啉衍生物会导致 PDAC 细胞中 P62 和 LC3-II 积累以及溶酶体碱化。此外，斑马鱼模型的体内毒性研究表明，所研究的 4-氨基喹啉的毒性低，无发育副作用，同时所应用的化合物有效抑制肿瘤生长并防止异种移植胰腺细胞的转移。总而言之，这些结果强调了 4-氨基喹啉作为一种特殊的结构，应该进一步研究其在胰腺癌治疗中的潜在应用。版权所有 © 2024。由 Elsevier B.V. 出版。

Common antimalarials such as artemisinins, chloroquine and their derivatives also possess potent anti-inflamantory, antiviral and anticancer properties. In the search for new therapeutics to combat difficult-to-treat pancreatic carcinomas, we unveiled that 4-aminoquinoline derivatives, with significant antiplasmodial properties and a great safety profile in vivo, have remarkable anticancer activity against pancreatic ductal adenocarcinoma (PDAC) and considerable efficacy in the xenograft model in vivo. The aim of the present study was to further investigate anticancer properties of these compounds in a drug-repurposing manner. The compounds showed profound cytotoxic effects at nanomolar to low micromolar concentration in 2D cultured cells (in vitro) and in the zebrafish PDAC xenograft model (in vivo). A deeper insight into their mechanisms of cytotoxic action showed these compounds induce apoptosis while increasing reactive oxygen species levels along with autophagy inhibition. Additional investigation of the autophagy modulation proved that tested quinoline derivatives cause P62 and LC3-II accumulation in PDAC cells alongside lysosomal alkalinization. Further, in vivo toxicity studies in the zebrafish model showed low toxicity without developmental side effects of the investigated 4-aminoquinolines, while the applied compounds effectively inhibited tumor growth and prevented the metastasis of xenografted pancreatic cells. Taken together, these results highlight the 4-aminoquinolines as privileged structures that ought to be investigated further for potential application in pancreatic carcinoma treatment.Copyright © 2024. Published by Elsevier B.V.