Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors
Ribonucleotide reductase is an effective target to overcome gemcitabine resistance in gemcitabine-resistant pancreatic cancer cells with dual resistant factors
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DOI：
10.1016/j.jphs.2015.01.006
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发表时间：
2015-03-01
影响因子：
3.5
通讯作者：
Yasuo, Takeda
中科院分区：
文献类型：
--
作者：
Minami, Kentaro;Shinsato, Yoshinari;Yasuo, Takeda
吉西他滨广泛用于治疗胰腺癌、肺癌和膀胱癌。然而，对吉西他滨的耐药性是有效化疗的一大障碍。据报道，核苷转运体、核苷和核苷酸代谢酶以及外排转运体与吉西他滨耐药有关。尽管大多数抗性因素被认为是相互关联的，但目前还不清楚一个因素如何影响另一个因素。在本研究中，我们建立了吉西他滨耐药的胰腺癌细胞株。这些细胞对吉西他滨的耐药性主要由两个过程引起：吉西他滨摄取减少和核糖核苷酸还原酶大亚基(RRM1)的过度表达。敲除RRM1，但不能过表达浓缩核苷转运蛋白1(CNT1)，则可完全克服吉西他滨的耐药性。在吉西他滨耐药细胞中敲除RRM1可以通过增加核苷转运体的表达来增加吉西他滨在细胞内的蓄积。此外，核糖核苷酸还原酶(RR)抑制剂羟基脲与吉西他滨对吉西他滨耐药细胞有协同作用。在这里，我们指出RR是克服吉西他滨耐药细胞中具有双重耐药因素的最有希望的靶点之一。(C)2015年日本药理学会。由爱思唯尔B.V.制作和托管。这是CC By-NC-ND许可证(http://creativecommons.org/licenses/by-nc-nd/4.0/).下的一篇开放获取文章
Gemcitabine is widely used for pancreatic, lung, and bladder cancer. However, drug resistance against gemcitabine is a large obstacle to effective chemotherapy. Nucleoside transporters, nucleoside and nucleotide metabolic enzymes, and efflux transporters have been reported to be involved in gemcitabine resistance. Although most of the resistant factors are supposed to be related to each other, it is unclear how one factor can affect the other one. In this study, we established gemcitabine-resistant pancreatic cancer cell lines. Gemcitabine resistance in these cells is caused by two major processes: a decrease in gemcitabine uptake and overexpression of ribonucleotide reductase large subunit (RRM1). Knockdown of RRM1, but not the overexpression of concentrative nucleoside transporter 1 (CNT1), could completely overcome the gemcitabine resistance. RRM1 knockdown in gemcitabine-resistant cells could increase the intracellular accumulation of gemcitabine by increasing the nucleoside transporter expression. Furthermore, a synergistic effect was observed between hydroxyurea, a ribonucleotide reductase (RR) inhibitor, and gemcitabine on the gemcitabine-resistant cells. Here we indicate that RR is one of the most promising targets to overcome gemcitabine resistance in gemcitabine-resistant cells with dual resistant factors. (C) 2015 Japanese Pharmacological Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).