Tao Li-Yang, Liang Yong-Ju, Wang Fang, Chen Li-Ming, Yan Yan-Yan, Dai Chun-Ling, Fu Li-Wu
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-Sen University, Guangzhou, China.
Cancer Chemother Pharmacol. 2009 Oct;64(5):961-9. doi: 10.1007/s00280-009-0949-1. Epub 2009 Mar 3.
Cediranib (recentin, AZD2171) is an oral small-molecule multiple receptor tyrosine kinases inhibitor. Here we investigate the ability of cediranib to reverse tumor multidrug resistance (MDR) due to overexpression of ABCB1 (P-glycoprotein) and ABCC1 (MRP1) transporters.
KBv200,MCF-7/adr, C-A120 and their parental sensitive cell lines KB, MCF-7 and KB-3-1 were used for reversal study. The intracellular accumulations of doxorubicin and rhodamine 123 were determined by flow cytometry. The expressions levels of ABCB1 and ABCC1 were investigated by Western blot and RT-PCR analyses. ATPase activity assay were performed by Luminescence. The functions of ERK in MCF-7/adr were investigated by RNA interference.
Cediranib significantly enhanced the sensitivity of ABCB1 or ABCC1 substrates in MDR cells, with no effect found on sensitive cells. However, the expressions of these transporters were not affected and the reversal activity of cediranib was not related to the phosphorylation of AKT or ERK1/2. Further studies showed that cediranib inhibited ATPase activity of ABCB1 (P-glycoprotein) in a dose-dependent manner.
Cediranib reverses ABCB1- and ABCC1-mediated MDR by directly inhibiting their drug efflux function. These findings may be useful for cancer combinational therapy with cediranib in the clinic.
西地尼布（RECENTIN，AZD2171）是一种口服小分子多受体酪氨酸激酶抑制剂。在此，我们研究西地尼布逆转因ABCB1（P-糖蛋白）和ABCC1（多药耐药相关蛋白1，MRP1）转运蛋白过表达所致肿瘤多药耐药（MDR）的能力。
采用KBv200、MCF-7/adr、C-A120及其亲本敏感细胞系KB、MCF-7和KB-3-1进行逆转研究。通过流式细胞术测定阿霉素和罗丹明123的细胞内蓄积量。采用蛋白质免疫印迹法和逆转录-聚合酶链反应（RT-PCR）分析研究ABCB1和ABCC1的表达水平。通过发光法进行ATP酶活性测定。采用RNA干扰研究细胞外调节蛋白激酶（ERK）在MCF-7/adr中的功能。
西地尼布显著增强了MDR细胞中ABCB1或ABCC1底物的敏感性，对敏感细胞无影响。然而，这些转运蛋白的表达未受影响，且西地尼布的逆转活性与蛋白激酶B（AKT）或ERK1/2的磷酸化无关。进一步研究表明，西地尼布以剂量依赖方式抑制ABCB1（P-糖蛋白）的ATP酶活性。
西地尼布通过直接抑制ABCB1和ABCC1的药物外排功能来逆转其介导的MDR。这些发现可能有助于西地尼布在临床上用于癌症联合治疗。
