Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo.
Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo.
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DOI：
10.1016/j.bcp.2014.02.012
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发表时间：
2014-05-01
影响因子：
5.8
通讯作者：
Chen, Zhe-Sheng
中科院分区：
文献类型：
--
作者：
Sodani, Kamlesh;Patel, Atish;Anreddy, Nagaraju;Singh, Satyakam;Yang, Dong-Hua;Kathawala, Rishil J.;Kumar, Priyank;Talele, Tanaji T.;Chen, Zhe-Sheng
多药耐药（MDR）是癌细胞对不同结构和作用机制的抗癌药物同时产生耐药性的现象。MDR已被证明与atp结合盒（ABC）转运体的过表达有关。在这里，我们报道了小分子酪氨酸激酶抑制剂telatinib通过抑制ABCG2外排转运蛋白活性来增强ABCG2底物抗癌药物的抗癌活性。过表达ABCG2的耐药细胞株与泰拉替尼和ABCG2底物抗癌药物共孵育可显著降低细胞活力，而单独使用泰拉替尼对药敏和耐药细胞株无显著影响。1 μM剂量的泰拉替尼对ABCG2过表达细胞株的ABCG2表达无显著影响。1 μM剂量的特拉替尼显著增强abcg2过表达细胞株细胞内[3H]-米托蒽醌（MX）的积累。此外，1 μM的替拉替尼可显著降低abcg2过表达细胞的[3H]-MX外排速率。此外，替拉替尼显著抑制ABCG2介导的ABCG2过表达膜囊中[3H]-E217βG的转运。特拉替尼以浓度依赖性的方式刺激ABCG2的atp酶活性，表明特拉替尼可能是ABCG2的底物。在同源模型人ABCG2的跨膜区发现了特拉替尼的结合相互作用。此外，替拉替尼（15 mg/kg）与阿霉素（1.8 mg/kg）可显著降低ABCG2过表达肿瘤在异种移植裸鼠模型中的生长速度和肿瘤大小。这些结果，假设它们可以翻译到人类，表明特拉替尼与特异性ABCG2底物药物联合可能对治疗过表达ABCG2的肿瘤有用。
Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1 μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1 μM significantly enhanced the intracellular accumulation of [3H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 μM significantly reduced the rate of [3H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [3H]-E217βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15 mg/kg) with doxorubicin (1.8 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.
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影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
--
作者：
Mross K;Frost A;Scheulen ME;Krauss J;Strumberg D;Schultheiss B;Fasol U;Büchert M;Krätzschmer J;Delesen H;Rajagopalan P;Christensen O
通讯作者：
Christensen O
影响因子：
2.6
作者：
Bliss, CI
通讯作者：
Bliss, CI
影响因子：
7.3
作者：
Diestra, JE;Scheffer, GL;Izquierdo, MA
通讯作者：
Izquierdo, MA
DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
通讯作者：
Chang G