Oliveri Valentina, Lanza Valeria, Milardi Danilo, Viale Maurizio, Maric Irena, Sgarlata Carmelo, Vecchio Graziella
Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.
Metallomics. 2017 Oct 18;9(10):1439-1446. doi: 10.1039/c7mt00156h.
Proliferation and programmed cell death are tightly correlated with the ubiquitin-proteasome system (UPS). Alterations in the UPS may be implicated in pathological conditions such as the proteasome over-activity in cancer cells. Mounting evidence indicates that many types of actively proliferating malignant cells are more sensitive to proteasome inhibition than normal cells, and therefore UPS inhibitors are actively pursued as anticancer agents. The approval of the proteasome inhibitor drug bortezomib for the treatment of myeloma and lymphoma further highlights the need for UPS inhibitors. Recent studies have suggested that clioquinol and 5-amino-8-hydroxyquinoline can inhibit proteasome activity and induce apoptosis in human cancer cells. As for clioquinol, a copper-dependent and -independent mechanism has been proposed to explain the inhibition of the proteasome whereas the activity of 5-amino-8-hydroxyquinoline has not been explored in the presence of copper(ii) ions. Herein, we investigated the biological activity of some 8-hydroxyquinolines by using human ovarian (A2780) and lung (A549) cancer cells. The effect of copper(ii) on the activity of these compounds was also evaluated. The investigated systems inhibit the chymotrypsin-like activity of the proteasome and induce growth inhibition and apoptosis in a concentration-dependent manner. Copper(ii) ions increase the activity of 8-hydroxyquinoline derivatives except in the case of 5-amino-8-hydroxyquinoline. This study suggests the great potential of amino- and chloro-8-hydroxyquinolines as anticancer agents. Furthermore, it clarifies some aspects concerning the activity of 5-amino-8-hydroxyquinoline, which has been previously proposed as a proteasome inhibitor capable of overcoming resistance to bortezomib.
细胞增殖与程序性细胞死亡与泛素 - 蛋白酶体系统（UPS）密切相关。UPS的改变可能与病理状况有关，如癌细胞中蛋白酶体的过度活跃。越来越多的证据表明，许多类型的活跃增殖恶性细胞比正常细胞对蛋白酶体抑制更敏感，因此UPS抑制剂正作为抗癌药物被积极研发。蛋白酶体抑制剂药物硼替佐米被批准用于治疗骨髓瘤和淋巴瘤，这进一步凸显了对UPS抑制剂的需求。最近的研究表明，氯碘羟喹和5 - 氨基 - 8 - 羟基喹啉可抑制蛋白酶体活性并诱导人癌细胞凋亡。对于氯碘羟喹，已提出一种铜依赖性和非依赖性机制来解释其对蛋白酶体的抑制作用，而5 - 氨基 - 8 - 羟基喹啉在铜（II）离子存在下的活性尚未被研究。在此，我们使用人卵巢（A2780）和肺癌（A549）细胞研究了一些8 - 羟基喹啉的生物活性。还评估了铜（II）对这些化合物活性的影响。所研究的体系抑制蛋白酶体的胰凝乳蛋白酶样活性，并以浓度依赖性方式诱导生长抑制和凋亡。除5 - 氨基 - 8 - 羟基喹啉外，铜（II）离子可增加8 - 羟基喹啉衍生物的活性。本研究表明氨基和氯代8 - 羟基喹啉作为抗癌药物具有巨大潜力。此外，它阐明了一些关于5 - 氨基 - 8 - 羟基喹啉活性的方面，该化合物先前被提议作为一种能够克服对硼替佐米耐药性的蛋白酶体抑制剂。
