Vodobatinib overcomes cancer multidrug resistance by attenuating the drug efflux function of ABCB1 and ABCG2

IF 4.2 3区 医学 Q1 PHARMACOLOGY & PHARMACY European journal of pharmacology Pub Date : 2025-02-05 DOI:10.1016/j.ejphar.2024.177231
Yen-Ching Li , Bing-Huan Lin , Megumi Murakami , Yu-Shan Wu , Tai-Ho Hung , Chin-Chuan Chen , Suresh V. Ambudkar , Chung-Pu Wu
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Abstract

Multidrug resistance (MDR) remains a significant obstacle in cancer treatment, primarily attributable to the overexpression of ATP-binding cassette (ABC) transporters such as ABCB1 and ABCG2 within cancer cells. These transporters actively diminish the effectiveness of cytotoxic drugs by facilitating ATP hydrolysis-dependent drug efflux, thereby reducing intracellular drug accumulation. Given the absence of approved treatments for multidrug-resistant cancers and the established benefits of combining tyrosine kinase inhibitors (TKIs) with conventional anticancer drugs, we investigate the potential of vodobatinib, a potent c-Abl TKI presently in clinical trials, to restore sensitivity to chemotherapeutic agents in multidrug-resistant cancer cells overexpressing ABCB1 and ABCG2. Results indicate that vodobatinib, administered at sub-toxic concentrations, effectively restores the sensitivity of multidrug-resistant cancer cells to cytotoxic drugs in a concentration-dependent manner. Moreover, vodobatinib enhances drug-induced apoptosis in these cells by inhibiting the drug-efflux function of ABCB1 and ABCG2, while maintaining their expression levels. Moreover, we found that while vodobatinib enhances the ATPase activity of ABCB1 and ABCG2, the overexpression of these transporters does not induce resistance to vodobatinib. These results strongly suggest that increased levels of ABCB1 or ABCG2 are unlikely to play a significant role in the development of resistance to vodobatinib in cancer patients. Overall, our findings unveil an additional pharmacological facet of vodobatinib against ABCB1 and ABCG2 activity, suggesting its potential incorporation into combination therapy for a specific subset of patients with tumors characterized by high ABCB1 or ABCG2 levels. Further investigation is warranted to fully elucidate the clinical implications of this therapeutic approach.

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Vodobatinib通过减弱ABCB1和ABCG2的药物外排功能来克服癌症多药耐药。
多药耐药(MDR)仍然是癌症治疗的一个重要障碍,主要是由于癌细胞内atp结合盒(ABC)转运体如ABCB1和ABCG2的过度表达。这些转运体通过促进ATP水解依赖的药物外排,从而减少细胞内药物积累,从而主动降低细胞毒性药物的有效性。鉴于缺乏针对多药耐药癌症的批准治疗方法,以及酪氨酸激酶抑制剂(TKIs)与常规抗癌药物联合使用的既定益处,我们研究了vodobatinib(一种目前处于临床试验中的强效c-Abl TKI)在过度表达ABCB1和ABCG2的多药耐药癌细胞中恢复对化疗药物敏感性的潜力。结果表明,以亚毒性浓度给药的伏多巴替尼可以有效地恢复多药耐药癌细胞对细胞毒性药物的敏感性,并呈浓度依赖性。此外,vodobatinib通过抑制ABCB1和ABCG2的药物外排功能,在维持其表达水平的同时,增强了这些细胞中药物诱导的凋亡。此外,我们发现虽然vodobatinib增强了ABCB1和ABCG2的atp酶活性,但这些转运体的过表达不会诱导对vodobatinib的抗性。这些结果强烈表明,ABCB1或ABCG2水平的升高不太可能在癌症患者对沃多巴替尼的耐药发展中发挥重要作用。总的来说,我们的研究结果揭示了vodobatinib对ABCB1和ABCG2活性的额外药理学方面,表明它可能结合到以高ABCB1或ABCG2水平为特征的肿瘤患者的特定亚群的联合治疗中。需要进一步的研究来充分阐明这种治疗方法的临床意义。
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来源期刊
CiteScore
9.00
自引率
0.00%
发文量
572
审稿时长
34 days
期刊介绍: The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems. The scope includes: Behavioural pharmacology Neuropharmacology and analgesia Cardiovascular pharmacology Pulmonary, gastrointestinal and urogenital pharmacology Endocrine pharmacology Immunopharmacology and inflammation Molecular and cellular pharmacology Regenerative pharmacology Biologicals and biotherapeutics Translational pharmacology Nutriceutical pharmacology.
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