Establishment and characterization of a bladder cancer cell line with enhanced doxorubicin resistance by mevalonate pathway activation

被引：25

作者：

Greife, Annemarie ^{[1
]}

Tukova, Jitka ^{[2
]}

Steinhoff, Christine ^{[3
]}

Scott, Simon D. ^{[4
]}

Schulz, Wolfgang A. ^{[1
]}

Hatina, Jiri ^{[1
,2
]}

机构：

[1] Univ Dusseldorf, Fac Med, Dept Urol, Dusseldorf, Germany

[2] Charles Univ Prague, Fac Med Pilsen, Dept Biol, Plzen 30166, Czech Republic

[3] Max Planck Inst Mol Genet, Dept Computat Biol, D-14195 Berlin, Germany

[4] Univ Kent, Medway Sch Pharm, Chatham, Kent, England

来源：

TUMOR BIOLOGY | 2015年 / 36卷 / 05期

关键词：

Bladder cancer; Chemotherapy; Doxorubicin resistance; Mevalonate pathway; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; UROTHELIAL CARCINOMA; DRUG-RESISTANCE; GENE-THERAPY; PHASE-III; STATINS; CHEMOTHERAPY; GEMCITABINE; SIMVASTATIN;

D O I：

10.1007/s13277-014-2959-9

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Resistance to chemotherapy is a major problem in the treatment of urothelial bladder cancer. Several mechanisms have been identified in resistance to doxorubicin by analysis of resistant urothelial carcinoma (UC) cell lines, prominently activation of drug efflux pumps and diminished apoptosis. We have derived a new doxorubicin-resistant cell line from BFTC-905 UC cells, designated BFTC-905-DOXO-II. A doxorubicin-responsive green fluorescent protein (GFP) reporter assay indicated that resistance in BFTC-905-DOXO-II was not due to increased drug efflux pump activity, whereas caspase-3/7 activation was indeed diminished. Gene expression microarray analysis revealed changes in proapoptotic and antiapoptotic genes, but additionally induction of the mevalonate (cholesterol) biosynthetic pathway. Treatment with simvastatin restored sensitivity of BFTC-905-DOXO-II to doxorubicin to that of the parental cell line. Induction of the mevalonate pathway has been reported as a mechanism of chemoresistance in other cancers; this is the first observation in bladder cancer. Combinations of statins with doxorubicin-containing chemotherapy regimens may provide a therapeutic advantage in such cases.

引用

页码：3293 / 3300

页数：8

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