Piska Kamil, Koczurkiewicz-Adamczyk Paulina, Kochanowski Paweł, Bobis-Wozowicz Sylwia, Władyka Benedykt, Pękala Elżbieta
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St, Krakow, Poland.
Doctoral School of Exact and Natural Sciences, Jagiellonian University, Krakow, Poland.
Med Oncol. 2025 Jul 8;42(8):315. doi: 10.1007/s12032-025-02893-0.
Anthracyclines are widely used anticancer agents with a complex mechanism of action involving topoisomerase II inhibition and DNA intercalation. Despite their clinical efficacy, their use is limited by cancer cell resistance, linked to the formation of secondary alcohol metabolites via carbonyl reductase 1 (CBR1)-mediated reduction. These metabolites exhibit reduced anticancer activity, positioning CBR1 as significant factor in determining therapy outcomes. The study aimed to elucidate the role of CBR1 in mediating the differential responses of various anthracyclines in cancer cells. The role of CBR1 in cancer resistance against five anthracyclines: doxorubicin, daunorubicin, epirubicin, idarubicin, and aclarubicin, was examined in A549 lung cancer cells transduced with the CBR1. Anthracyclines were found to present significant differences in activity related to CBR1 overexpression. Surprisingly, aclarubicin was the most dependent on CBR1 among the tested compounds, while it exhibited a low reaction velocity when catalyzed by recombinant CBR1. The findings reveal critical differences in anthracycline susceptibility to CBR1, offering insights into resistance mechanisms.
蒽环类药物是广泛使用的抗癌药物，其作用机制复杂，涉及拓扑异构酶II抑制和DNA嵌入。尽管它们具有临床疗效，但由于癌细胞耐药性，其应用受到限制，这种耐药性与通过羰基还原酶1（CBR1）介导的还原作用形成二级醇代谢物有关。这些代谢物的抗癌活性降低，使CBR1成为决定治疗结果的重要因素。该研究旨在阐明CBR1在介导癌细胞对各种蒽环类药物的不同反应中的作用。在用CBR1转导的A549肺癌细胞中检测了CBR1在癌症对五种蒽环类药物（阿霉素、柔红霉素、表柔比星、伊达比星和阿克拉霉素）耐药中的作用。发现蒽环类药物在与CBR1过表达相关的活性方面存在显著差异。令人惊讶的是，在测试的化合物中，阿克拉霉素对CBR1的依赖性最强，而当由重组CBR1催化时，它的反应速度较低。这些发现揭示了蒽环类药物对CBR1敏感性的关键差异，为耐药机制提供了见解。
