Mioč Marija, Beus Maja, Carević Karla, Rajić Zrinka, Sarkadi Balázs, Telbisz Ágnes, Kralj Marijeta
Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička c. 54, 10000 Zagreb, Croatia.
Department of Medicinal Chemistry, University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kovačića 1, 10000 Zagreb, Croatia.
Int J Mol Sci. 2025 Jun 3;26(11):5367. doi: 10.3390/ijms26115367.
Multidrug resistance (MDR) poses a significant challenge in cancer therapy, often leading to treatment failure and relapse. ATP-binding cassette (ABC) transporters, particularly ABCG2, play a pivotal role in MDR development by actively expelling chemotherapeutic agents from cancer cells. This study investigates the effects of two groups of primaquine derivatives-fumardiamides (-) and -ureas (, ), both bearing halogenated benzene rings-on the activity of P-glycoprotein (P-gp) and ABCG2. Their potential to reverse MDR was evaluated through a series of functional assays aimed at comparing transporter-compound interactions. The results indicated that fumardiamide derivatives, specifically , , and , exhibited potent inhibition of ABCG2 while having no effect on P-gp, demonstrating a selective mode of action. The tested derivatives displayed low to moderate cytotoxicity and did not affect ABCG2 expression or localization. Moreover, these compounds enhanced the sensitivity of drug-resistant cancer cell lines to mitoxantrone, underscoring their potential to overcome ABCG2-mediated MDR. These findings suggest that chemical modifications of primaquine, particularly the incorporation of fumardiamide moieties, confer novel biological properties, providing promising leads for the development of selective ABCG2 inhibitors.
多药耐药性（MDR）在癌症治疗中构成了重大挑战，常常导致治疗失败和复发。ATP结合盒（ABC）转运蛋白，尤其是ABCG2，通过将化疗药物从癌细胞中主动排出，在MDR的发展中起关键作用。本研究调查了两组均带有卤代苯环的伯氨喹衍生物——富马二酰胺（-）和脲（，）对P-糖蛋白（P-gp）和ABCG2活性的影响。通过一系列旨在比较转运蛋白与化合物相互作用的功能测定，评估了它们逆转MDR的潜力。结果表明，富马二酰胺衍生物，特别是，和，对ABCG2表现出强效抑制作用，而对P-gp没有影响，显示出一种选择性作用模式。所测试的衍生物表现出低至中等的细胞毒性，并且不影响ABCG2的表达或定位。此外，这些化合物增强了耐药癌细胞系对米托蒽醌的敏感性，突出了它们克服ABCG2介导的MDR的潜力。这些发现表明，伯氨喹的化学修饰，特别是引入富马二酰胺基团，赋予了新的生物学特性，为开发选择性ABCG2抑制剂提供了有前景的线索。
