Čermáková Lucie, Hofman Jakub, Laštovičková Lenka, Havlíčková Lucie, Špringrová Ivona, Novotná Eva, Wsól Vladimír
Department of Biochemical Sciences, Faculty of Pharmacy, Charles University, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Charles University, Akademika Heyrovskeho 1203, 50005 Hradec Kralove, Czech Republic.
Pharmaceutics. 2022 Sep 21;14(10):1994. doi: 10.3390/pharmaceutics14101994.
Zanubrutinib (ZAN) is a Bruton's tyrosine kinase inhibitor recently approved for the treatment of some non-Hodgkin lymphomas. In clinical trials, ZAN is often combined with standard anthracycline (ANT) chemotherapy. Although ANTs are generally effective, drug resistance is a crucial obstacle that leads to treatment discontinuation. This study showed that ZAN counteracts ANT resistance by targeting aldo-keto reductase 1C3 (AKR1C3) and ATP-binding cassette (ABC) transporters. AKR1C3 catalyses the transformation of ANTs to less potent hydroxy-metabolites, whereas transporters decrease the ANT-effective concentrations by pumping them out of the cancer cells. In our experiments, ZAN inhibited the AKR1C3-mediated inactivation of daunorubicin (DAUN) at both the recombinant and cellular levels. In the drug combination experiments, ZAN synergistically sensitised AKR1C3-expressing HCT116 and A549 cells to DAUN treatment. Gene induction studies further confirmed that ZAN did not increase the intracellular level of AKR1C3 mRNA; thus, the drug combination effect is not abolished by enzyme induction. Finally, in accumulation assays, ZAN was found to interfere with the DAUN efflux mediated by the ABCB1, ABCG2, and ABCC1 transporters, which might further contribute to the reversal of ANT resistance. In summary, our data provide the rationale for ZAN inclusion in ANT-based therapy and suggest its potential for the treatment of tumours expressing AKR1C3 and/or the above-mentioned ABC transporters.
泽布替尼（ZAN）是一种布鲁顿酪氨酸激酶抑制剂，最近被批准用于治疗某些非霍奇金淋巴瘤。在临床试验中，ZAN常与标准蒽环类（ANT）化疗联合使用。尽管ANTs通常有效，但耐药性是导致治疗中断的关键障碍。本研究表明，ZAN通过靶向醛酮还原酶1C3（AKR1C3）和ATP结合盒（ABC）转运蛋白来对抗ANT耐药性。AKR1C3催化ANTs转化为效力较低的羟基代谢物，而转运蛋白则通过将ANTs泵出癌细胞来降低其有效浓度。在我们的实验中，ZAN在重组水平和细胞水平上均抑制了柔红霉素（DAUN）的AKR1C3介导的失活。在药物联合实验中，ZAN协同使表达AKR1C3的HCT116和A549细胞对DAUN治疗敏感。基因诱导研究进一步证实，ZAN不会增加AKR1C3 mRNA的细胞内水平；因此，酶诱导不会消除药物联合效应。最后，在积累试验中，发现ZAN会干扰由ABCB1、ABCG2和ABCC1转运蛋白介导的DAUN外排，这可能进一步有助于逆转ANT耐药性。总之，我们的数据为将ZAN纳入基于ANT的治疗提供了理论依据，并表明其在治疗表达AKR1C3和/或上述ABC转运蛋白的肿瘤方面的潜力。
