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Lansoprazole (LPZ) reverses multidrug resistance (MDR) in cancer through impeding ATP-binding cassette (ABC) transporter-mediated chemotherapeutic drug efflux and lysosomal sequestration
Drug Resistance Updates ( IF 15.8 ) Pub Date : 2024-06-04 , DOI: 10.1016/j.drup.2024.101100 Ning Ji 1 , Hui Li 2 , Yixuan Zhang 2 , Yuelin Li 2 , Peiyu Wang 2 , Xin Chen 2 , Yi-Nan Liu 2 , Jing-Quan Wang 3 , Yuqi Yang 3 , Zhe-Sheng Chen 3 , Yueguo Li 1 , Ran Wang 2 , Dexin Kong 2
Drug Resistance Updates ( IF 15.8 ) Pub Date : 2024-06-04 , DOI: 10.1016/j.drup.2024.101100 Ning Ji 1 , Hui Li 2 , Yixuan Zhang 2 , Yuelin Li 2 , Peiyu Wang 2 , Xin Chen 2 , Yi-Nan Liu 2 , Jing-Quan Wang 3 , Yuqi Yang 3 , Zhe-Sheng Chen 3 , Yueguo Li 1 , Ran Wang 2 , Dexin Kong 2
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Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, and . Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR . Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.
中文翻译：
兰索拉唑 (LPZ) 通过阻碍 ATP 结合盒 (ABC) 转运蛋白介导的化疗药物流出和溶酶体隔离来逆转癌症的多药耐药性 (MDR)
兰索拉唑是众多质子泵抑制剂 (PPI) 中的一种，与 ABCB1 和 ABCG2 作用更强。本研究旨在探讨兰索拉唑在逆转癌症中 ABCB1/G2 介导的 MDR 的潜力。进行逆转研究和组合评估以确定兰索拉唑的协同抗 MDR 作用。溶酶体染色用于测定兰索拉唑对 ABCB1 介导的溶酶体隔离的影响。进行底物积累和外排测定、ATP酶活性和分子对接来评估兰索拉唑对ABCB1/G2功能的影响。 Western blot和免疫荧光检测兰索拉唑对ABCB1/G2表达及亚细胞定位的影响。建立MDR裸鼠模型，评价兰索拉唑对MDR的影响。兰索拉唑可减弱 ABCB1/G2 介导的 MDR，并在 MDR 细胞中与底物药物表现出协同作用。实验表明，兰索拉唑可减弱 ABCB1/G2 介导的 MDR，并表现出协同作用，增强 ABCB1/G2 介导环境中底物抗癌药物的敏感性，且无明显毒性。兰索拉唑阻碍了 ABCB1 介导的溶酶体隔离，导致底物药物的细胞内积累大幅增加。兰索拉唑的作用并非归因于 ABCB1/G2 亚细胞定位的下调或改变。兰索拉唑促进 ABCB1/G2 的 ATPase 活性，并竞争性地与 ABCB1/G2 的底物结合区域结合。这些发现提出了新的治疗途径，兰索拉唑和化疗药物的组合可以减轻 ABCB1/G2 过表达介导的 MDR。
更新日期：2024-06-04
中文翻译：
兰索拉唑 (LPZ) 通过阻碍 ATP 结合盒 (ABC) 转运蛋白介导的化疗药物流出和溶酶体隔离来逆转癌症的多药耐药性 (MDR)
兰索拉唑是众多质子泵抑制剂 (PPI) 中的一种，与 ABCB1 和 ABCG2 作用更强。本研究旨在探讨兰索拉唑在逆转癌症中 ABCB1/G2 介导的 MDR 的潜力。进行逆转研究和组合评估以确定兰索拉唑的协同抗 MDR 作用。溶酶体染色用于测定兰索拉唑对 ABCB1 介导的溶酶体隔离的影响。进行底物积累和外排测定、ATP酶活性和分子对接来评估兰索拉唑对ABCB1/G2功能的影响。 Western blot和免疫荧光检测兰索拉唑对ABCB1/G2表达及亚细胞定位的影响。建立MDR裸鼠模型，评价兰索拉唑对MDR的影响。兰索拉唑可减弱 ABCB1/G2 介导的 MDR，并在 MDR 细胞中与底物药物表现出协同作用。实验表明，兰索拉唑可减弱 ABCB1/G2 介导的 MDR，并表现出协同作用，增强 ABCB1/G2 介导环境中底物抗癌药物的敏感性，且无明显毒性。兰索拉唑阻碍了 ABCB1 介导的溶酶体隔离，导致底物药物的细胞内积累大幅增加。兰索拉唑的作用并非归因于 ABCB1/G2 亚细胞定位的下调或改变。兰索拉唑促进 ABCB1/G2 的 ATPase 活性，并竞争性地与 ABCB1/G2 的底物结合区域结合。这些发现提出了新的治疗途径，兰索拉唑和化疗药物的组合可以减轻 ABCB1/G2 过表达介导的 MDR。
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