ATP结合盒（ABC）药物外排转运蛋白和药物代谢酶在药物动力学药物相互作用和多药耐药性（MDR）中发挥关键作用。塔泽替尼（EPZ-6438，Tazverik）是一种新型表观遗传学药物，最近批准用于治疗晚期上皮样肉瘤和滨胶样淋巴瘤。此外，目前正在对这种药物进行临床试验，以治疗非小细胞肺癌（NSCLC）等多种其他癌症。本研究旨在调查塔泽替尼对特定ABC转运蛋白/细胞色素P450 3A4（CYP3A4）酶的抑制作用，以全面探索其在MDR中的作用。首先，我们的积累和分子对接研究表明，塔泽替尼是ABC B1，ABCC1和ABCG2转运蛋白的独特三重抑制剂。相比之下，塔泽替尼与CYP3A4同工酶的相互作用水平很低。药物组合实验证实，塔泽替尼是一种多靶点的MDR调控剂，能够与多种传统化疗药物在体外协同作用。随后的半胱氨酸激活酶活性实验和细胞核凋亡染色证明，有效诱导凋亡是观察到的协同作用背后的原因。值得注意的是，在从患者活检样品中生成的原发性体外非小细胞肺癌移植物上记录到了塔泽替尼的强大MDR调控能力。相反，在比较增殖实验中排除了该药物作为药物动力学MDR的受害者的可能性。最后，在NSCLC细胞系中测试的药物未被确定为耐药表型的诱导剂。总之，我们证明了塔泽替尼是一种独特的多靶点化疗增敏剂，具有强大的潜力，可以克服传统MDR调控剂时代的局限性。版权所有 © 2023。由Elsevier Inc.出版。

ATP-binding cassette (ABC) drug efflux transporters and drug metabolizing enzymes play crucial roles in pharmacokinetic drug-drug interactions and multidrug tumor resistance (MDR). Tazemetostat (EPZ-6438, Tazverik) is a novel epigenetic drug that has been recently approved for the therapy of advanced epithelioid sarcoma and follicular lymphoma. Additionally, this medication is currently being clinically tested to treat several other cancers such as non-small cell lung cancer (NSCLC). This study aimed to investigate the inhibitory effects of tazemetostat on selected ABC transporters/cytochrome P450 3A4 (CYP3A4) enzyme to comprehensively explore its role in MDR. First, our accumulation and molecular docking studies showed that tazemetostat is a unique triple inhibitor of ABCB1, ABCC1, and ABCG2 transporters. In contrast, tazemetostat exhibited only low level of interaction with the CYP3A4 isozyme. Drug combination assays confirmed that tazemetostat is a multipotent MDR modulator able to synergize with various conventional chemotherapeutics in vitro. Subsequent caspase activity assays and microscopic staining of apoptotic nuclei proved that the effective induction of apoptosis is behind the observed synergies. Notably, a potent MDR-modulatory capacity of tazemetostat was recorded in primary ex vivo NSCLC explants generated from patients' biopsies. On the contrary, its possible position of pharmacokinetic MDR's victim was excluded in comparative proliferation assays. Finally, tested drug has not been identified as an inducer of resistant phenotype in NSCLC cell lines. In conclusion, we demonstrated that tazemetostat is a unique multispecific chemosensitizer, which has strong potential to overcome limitations seen in the era of traditional MDR modulators.Copyright © 2023. Published by Elsevier Inc.