A Potent Chemotherapeutic Strategy with Eg5 Inhibitor against Gemcitabine Resistant Bladder Cancer.
A Potent Chemotherapeutic Strategy with Eg5 Inhibitor against Gemcitabine Resistant Bladder Cancer.
复制标题
使用 Eg5 抑制剂对抗吉西他滨耐药膀胱癌的有效化疗策略。
DOI：
10.1371/journal.pone.0144484
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ding S
中科院分区：
文献类型：
--
作者：
Sun L;Lu J;Niu Z;Ding K;Bi D;Liu S;Li J;Wu F;Zhang H;Zhao Z;Ding S
对吉西他滨的耐药是膀胱癌治疗中的主要问题，其机制仍不清楚。Eg 5是近年来发现的一个有吸引力的肿瘤化疗靶点，因此Eg 5抑制剂的新型靶向化疗有望改善吉西他滨耐药膀胱癌的抗癌效果。在这项研究中，RT 112-Gr细胞对吉西他滨的敏感性比亲本细胞系低350倍，而KU 7-Gr细胞对吉西他滨的敏感性比亲本细胞系低15倍。进行人类OneArray微阵列分析以获得关于在RT 112和RT 112-Gr细胞中差异表达的基因的广谱信息。使用细胞活力测定在RT 112-Gr细胞系中分析S（MeO）TLC（Eg 5抑制剂）的抗增殖活性。此外，使用皮下异种移植肿瘤模型在体内评价抑制作用。根据人类OneArray®基因芯片的结果，RRM 1和RRM 2上调，而Eg 5没有显著变化。台盼蓝染色证实，S（MeO）TLC和吉西他滨联合S（MeO）TLC组中RT 112-Gr细胞的细胞活力与其他组相比显著降低。S（MeO）TLC和S（MeO）TLC+吉西他滨组与其他组相比在体内显著抑制肿瘤生长。S（MeO）TLC组和吉西他滨+S（MeO）TLC组在体内外对膀胱癌的抑制作用无显著性差异。我们的数据共同表明，S（MeO）TLC代表了一种治疗吉西他滨耐药膀胱癌的新策略。
Development of resistance to gemcitabine is a major concern in bladder cancer therapy, and the mechanism remains unclear. Eg5 has been recently identified as an attractive target in cancer chemotherapy, so novel targeted chemotherapy with Eg5 inhibitor is expected to improve the anticancer effect in gemcitabine-resistant bladder cancer. In this research, RT112-Gr cells were 350-fold less sensitive to gemcitabine than the parental cell lines, while KU7-Gr cells were 15-fold less sensitive to gemcitabine than the parental cell lines. Human OneArray Microarray analysis was performed to obtain broad spectrum information about the genes differentially expressed in RT112 and RT112-Gr cells. The anti-proliferative activity of S(MeO)TLC, an Eg5 inhibitor, was analyzed in RT112-Gr cell lines using a cell viability assay. Furthermore, the inhibitory effect was evaluated in vivo using subcutaneous xenograft tumor model. According to the result of Human OneArray® GeneChip, RRM1 and RRM2 were up-regulated, while there was no significant change in Eg5. Trypan blue staining confirmed that in S(MeO)TLC and Gemcitabine combining S(MeO)TLC group cell viability were significantly decreased in RT112-Gr cells as compared with other groups. S(MeO)TLC and S(MeO)TLC+gemcitabine groups prominently suppressed tumor growth in comparison with other groups’ in vivo. There were no significant differences in S(MeO)TLC and gemcitabine+S(MeO)TLC group in the effect of inhibition of bladder cancer in vivo and in vitro. Our data collectively demonstrated that S(MeO)TLC represents a novel strategy for the treatment of gemcitabine resistant bladder cancer.