Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells.
Disulfiram targets cancer stem-like cells and reverses resistance and cross-resistance in acquired paclitaxel-resistant triple-negative breast cancer cells.
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DOI：
10.1038/bjc.2013.534
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发表时间：
2013-10-01
影响因子：
8.8
通讯作者：
Wang, W.
中科院分区：
文献类型：
--
作者：
Liu, P.;Kumar, I. S.;Brown, S.;Kannappan, V.;Tawari, P. E.;Tang, J. Z.;Jiang, W.;Armesilla, A. L.;Darling, J. L.;Wang, W.
三阴性乳腺癌（TNBC）预后明显较差。获得性耐药性仍然是TNBC治疗失败的主要原因。在临床上，复发的TNBC通常对多种药物具有泛耐药性，其耐药机制完全不同。针对泛耐药的机制研究和新药开发将有可能改善TNBC患者的治疗结果。本研究采用MTT法、结合指数（CI）-等效线图、Western blot、ALDEFLUOR分析、克隆形成试验和免疫细胞化学等方法。耐药MDA-MB-231 PAC 10细胞对紫杉醇（PAC）、顺铂（CDDP）、多西他赛和阿霉素具有高度交叉耐药。MDA-MB-231 PAC 10细胞处于静止状态，倍增时间显著延长（64.9 vs 31.7 h）。这可能与p21 Waf 1的高表达有关。MDA-MB-231 PAC 10细胞表达高醛脱氢酶（ALDH）活性和一组胚胎干细胞相关蛋白，例如Oct 4、Sox 2、Nanog以及HIF 2 α和NF-κ Bp 65的核化。我们以前曾报道过，双硫仑（DS），一种抗酒精中毒药物，靶向癌症干细胞（CSC）和增强抗癌药物的细胞毒性。双硫仑可完全逆转MDA-MB-231 PAC 10细胞对PAC和CDDP的耐药性。癌症干细胞可能是获得性泛耐药性的原因。DS作为一种临床应用药物，可作为CSC抑制剂逆转获得性泛耐药。
Triple-negative breast cancer (TNBC) has significantly worse prognosis. Acquired chemoresistance remains the major cause of therapeutic failure of TNBC. In clinic, the relapsed TNBC is commonly pan-resistant to various drugs with completely different resistant mechanisms. Investigation of the mechanisms and development of new drugs to target pan-chemoresistance will potentially improve the therapeutic outcomes of TNBC patients. In this study, 1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)–isobologram, western blot, ALDEFLUOR analysis, clonogenic assay and immunocytochemistry were used. The chemoresistant MDA-MB-231PAC10 cells are highly cross-resistant to paclitaxel (PAC), cisplatin (CDDP), docetaxel and doxorubicin. The MDA-MB-231PAC10 cells are quiescent with significantly longer doubling time (64.9 vs 31.7 h). This may be caused by high expression of p21Waf1. The MDA-MB-231PAC10 cells express high aldehyde dehydrogenase (ALDH) activity and a panel of embryonic stem cell-related proteins, for example, Oct4, Sox2, Nanog and nuclealisation of HIF2α and NF-κBp65. We have previously reported that disulfiram (DS), an antialcoholism drug, targets cancer stem cells (CSCs) and enhances cytotoxicity of anticancer drugs. Disulfiram abolished CSC characters and completely reversed PAC and CDDP resistance in MDA-MB-231PAC10 cells. Cancer stem cells may be responsible for acquired pan-chemoresistance. As a drug used in clinic, DS may be repurposed as a CSC inhibitor to reverse the acquired pan-chemoresistance.
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影响因子：
2.5
作者：
Dean, Michael
通讯作者：
Dean, Michael
影响因子：
50.3
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
通讯作者：
Cordon-Cardo C
DOI：
10.1007/bf01877380
发表时间：
1993-01-01
期刊：
BIOTHERAPY
影响因子：
--
作者：
DUFOUR, P;LANG, JM;OBERLING, F
通讯作者：
OBERLING, F
影响因子：
8
作者：
Knuefermann, C;Lu, Y;Fan, Z
通讯作者：
Fan, Z
影响因子：
78.5
作者：
Bjerkvig, R;Tysnes, BB;Terzis, AJA
通讯作者：
Terzis, AJA