The FLT3 inhibitor midostaurin selectively resensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic agents.
FLT3 抑制剂 mido in 选择性地将 ABCB1-overexpressing 多药耐药癌细胞重新敏感至传统化疗药物。
Chemoresistance Combination chemotherapy with PKC412 Drug repositioning Modulator P-glycoprotein
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摘要

The occurrence of multidrug resistance (MDR) associated with the overexpression of the ATP-binding cassette (ABC) protein ABCB1 in cancer cells remains a significant obstacle to successful cancer chemotherapy. Therefore, discovering modulators that are capable of inhibiting the drug efflux function or expression of ABCB1 and re-sensitizing multidrug-resistant cancer cells to anticancer agents is of great clinical importance. Regrettably, due to potential adverse events associated with drug-drug interactions and toxicity in patients, researchers have struggled to develop a synthetic inhibitor of ABCB1 that is clinically applicable to improve the effectiveness of chemotherapy. Alternatively, through drug repositioning of approved drugs, we discovered that the FMS-like tyrosine kinase-3 (FLT3) inhibitor midostaurin blocks the drug transport function of ABCB1 and re-sensitizes ABCB1-overexpressing multidrug-resistant cancer cells to conventional chemotherapeutic drugs. Our findings were further supported by results demonstrating that midostaurin potentiates drug-induced apoptosis in ABCB1-overexpressing cancer cells and inhibits the ATPase activity of ABCB1. Considering that midostaurin is a clinically approved anticancer agent, our findings revealed an additional action of midostaurin and that patients with multidrug-resistant tumors may benefit from a combination therapy of midostaurin with standard chemotherapy, which should be further investigated.

译文

与肿瘤细胞中 ATP 结合盒 (ABC) 蛋白 ABCB1 的过表达相关的多药耐药性 (MDR) 的发生仍然是癌症化疗成功的一个重要障碍。因此,发现能够抑制药物外排功能或 ABCB1 表达并使多药耐药癌细胞对抗癌药物重新敏感的调节剂具有重要的临床意义。遗憾的是,由于与患者的药物相互作用和毒性相关的潜在不良事件,研究人员一直在努力开发一种临床适用于提高化疗有效性的合成 ABCB1 抑制剂。或者,通过已批准药物的药物重新定位,我们发现 FMS 样酪氨酸激酶-3 (FLT3) 抑制剂 mido 'in 阻断 ABCB1 的药物转运功能,并使 ABCB1-overexpressing 多药耐药癌细胞对常规化疗药物重新敏感。我们的发现得到了进一步的支持,结果表明米多辛加强了药物诱导的 ABCB1-overexpressing 癌细胞的凋亡,并抑制了 abcb1 的 atp 酶活性。考虑到米朵素是一种临床认可的抗癌药物,我们的研究结果揭示了米朵素的额外作用以及多重耐药肿瘤患者可能受益于米朵素与标准化疗的联合治疗, 这应该进一步调查。

Midostaurin

肿瘤 白血病 药物
概述  :  

2017年4月28日,美国食品药品管理局(FDA)批准了米哚妥林上市,用于治疗FLT3+的急性髓系白血病(AML)。米哚妥林是由瑞士诺华生产的,是25年来AML首款新药,也是第一款与化疗联用治疗AML的靶向药物。米哚妥林是多种激酶抑制剂,能抑制包括FLT3、PKC、C-FOS、MAPK、PDGFR、CDK1、KIT、VEGF等多种激酶活性。   国际多中心FLT3+ AML 3期临床试验中,研究人员检测了3277例AML,招募了其中符合要求的717例FLT3+患者,并将他们随机

Midostaurin 

释    义   n. 米哚妥林

例    句   The natural history of FLT3-mutated AML is changing after the approval of midostaurin for frontline therapy and gilteritinib for relapsed or refractory patients. 在米哚妥林和吉特替尼被批准用于一线治疗和复发或难治性患者后,FLT3突变的AML的自然史正在改变。

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