Selective Inhibition of the ABCG2 Transporter by Primaquine Derivatives Reverses the Multidrug Resistance of Tumor Cells

Mioč, Marija; Beus, Maja; Carević, Karla; Rajić, Zrinka; Sarkadi, Balázs; Telbisz, Ágnes; Kralj, Marijeta (2025) Selective Inhibition of the ABCG2 Transporter by Primaquine Derivatives Reverses the Multidrug Resistance of Tumor Cells. International Journal of Molecular Sciences, 26 (11). ISSN 1422-0067

PDF - Published Version - article Available under License Creative Commons Attribution. Download (7MB)

Abstract

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 (1a–d) and bis-ureas (2a, b), 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 1a, 1b, and 1d, 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.

Item Type:	Article
Uncontrolled Keywords:	ATP-binding cassette (ABC) transporters; ABCG2; P-glycoprotein; multidrug resistance; primaquine derivatives; in vitro functional studies
Subjects:	BIOMEDICINE AND HEALTHCARE > Basic Medical Sciences
Divisions:	Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Mulitidisciplinarni pristup otkriću lijekova s ciljanim djelovanjem na matične stanice tumora – uloga transporta kalija-MultiCaST Marijeta Kralj IP-2013-11-5660 HRZZ Jačanje znanstveno-istraživačkih i inovacijskih kapaciteta Farmaceutsko-biokemijskog fakulteta Sveučilišta u Zagrebu-FarmInova Jasmina Lovrić KK.01.1.1.02.0021 EK
Depositing User:	Lorena Palameta
Date Deposited:	02 Sep 2025 09:08
URI:	http://fulir.irb.hr/id/eprint/9951
DOI:	10.3390/ijms26115367

Actions (login required)

View Item