Franko Ondrej, Čižmáriková Martina, Kello Martin, Michalková Radka, Wesołowska Olga, Środa-Pomianek Kamila, Marques Sérgio M, Bednář David, Háziková Viktória, Liška Tomáš Ján, Habalová Viera
Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 11 Košice, Slovakia.
Department of Biophysics and Neurobiology, Wroclaw Medical University, 50-369 Wrocław, Poland.
Int J Mol Sci. 2025 Apr 27;26(9):4138. doi: 10.3390/ijms26094138.
Chalcones, potential anticancer agents, have shown promise in the suppression of multidrug resistance due to the inhibition of drug efflux driven by certain adenosine triphosphate (ATP)-binding cassette (ABC) transporters. The gene and protein expression of chosen ABC transporters (multidrug resistance protein 1, ABCB1; multidrug resistance-associated protein 1, ABCC1; and breast cancer resistance protein, ABCG2) in human colorectal cancer cells (COLO 205 and COLO 320, which overexpress active ABCB1) was mainly studied in this work under the influence of a novel synthetic acridine-based chalcone, 1C. While gene expression dropped just at 24 h, compound 1C selectively suppressed colorectal cancer cell growth and greatly lowered ABCB1 protein levels in COLO 320 cells at 24, 48, and 72 h. It also reduced ABCC1 protein levels after 48 h. Molecular docking and ATPase tests show that 1C probably acts as an allosteric modulator of ABCB1. It also lowered galectin-1 (GAL1) expression in COLO 205 cells at 24 h. Functional tests on COLO cells revealed ABCB1 and ABCC1/2 to be major contributors to multidrug resistance in both. Overall, 1C transiently lowered GAL1 in COLO 205 while affecting important functional ABC transporters, mostly ABCB1 and to a lesser extent ABCC1 in COLO 320 cells. COLO 320's absence of GAL1 expression points to a possible yet unknown interaction between GAL1 and ABCB1.
查耳酮是潜在的抗癌药物，由于其能够抑制某些三磷酸腺苷（ATP）结合盒（ABC）转运蛋白驱动的药物外排，在抑制多药耐药方面显示出前景。在这项工作中，主要研究了新型合成的基于吖啶的查耳酮1C对人结肠癌细胞（COLO 205和COLO 320，这两种细胞过表达活性ABCB1）中所选ABC转运蛋白（多药耐药蛋白1，ABCB1；多药耐药相关蛋白1，ABCC1；以及乳腺癌耐药蛋白，ABCG2）的基因和蛋白表达的影响。虽然基因表达仅在24小时时下降，但化合物1C在24、48和72小时时选择性地抑制结肠癌细胞生长，并大大降低COLO 320细胞中ABCB1蛋白水平。它在48小时后还降低了ABCC1蛋白水平。分子对接和ATP酶测试表明，1C可能作为ABCB1的变构调节剂发挥作用。它在24小时时还降低了COLO 205细胞中半乳糖凝集素-1（GAL1）的表达。对COLO细胞的功能测试表明，ABCB1和ABCC1/2是这两种细胞中多药耐药的主要原因。总体而言，1C在COLO 205中短暂降低GAL1，同时影响重要的功能性ABC转运蛋白，在COLO 320细胞中主要是ABCB1，其次是ABCC1。COLO 320中缺乏GAL1表达表明GAL1与ABCB1之间可能存在未知的相互作用。
