下调核因子κB激活是获得性铂耐药膀胱癌的一种有效治疗方式。

Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer.

作者信息

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Suzuki Eriko, Mizuno Ryuichi, Shinojima Toshiaki, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

机构信息

Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Department of Applied Biological Science, Tokyo University of Agriculture and Technology, 3-8-1 Harumi-cho, Fuchu-shi, Tokyo, 183-8538, Japan.

出版信息

BMC Cancer. 2015 Apr 29;15:324. doi: 10.1186/s12885-015-1315-9.

DOI:10.1186/s12885-015-1315-9

PMID:25926105

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4424446/

Abstract

BACKGROUND

No previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells.

METHODS

Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro.

RESULTS

Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively.

CONCLUSION

There was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer.

摘要

背景

既往尚无研究探讨膀胱肿瘤对顺铂治疗产生获得性耐药时，NF-κB阻断的疗效。我们研究了新型NF-κB抑制剂环氧喹霉素脱羟甲基衍生物（DHMEQ）对顺铂耐药膀胱癌细胞中NF-κB激活的影响及其治疗作用。

方法

使用两个人侵袭性膀胱癌细胞系T24和T24PR。T24PR细胞系是通过在含顺铂的培养基中培养6个月新建立的获得性铂耐药亚系。通过蛋白质印迹分析确定两个分级细胞系中核内p65蛋白的表达。通过电泳迁移率变动分析检测NF-κB的DNA结合活性。在体内和体外分析细胞毒性作用和凋亡诱导情况。

结果

与T24细胞相比，T24PR细胞中p65的核内表达和DNA结合活性明显增强，且二者均被DHMEQ显著抑制。与亲本细胞相比，在这些化疗耐药细胞中单独用DHMEQ处理可观察到细胞活力降低和强烈的凋亡诱导。由于在体外研究中T24PR细胞对紫杉醇未表现出明显的交叉耐药，我们接下来研究DHMEQ与紫杉醇联合应用是否能增强紫杉醇治疗T24PR肿瘤的疗效。使用小鼠异种移植模型，用DHMEQ（2mg/kg）和紫杉醇（10mg/kg）联合治疗的肿瘤平均体积明显小于单独用紫杉醇治疗的肿瘤（p<0.05），与溶剂对照相比，联合应用DHMEQ和紫杉醇治疗的小鼠肿瘤体积减少率分别为66.9%和17.0%。