Down-regulation of MDR1 by Ad-DKK3 via Akt/NFκB pathways augments the anti-tumor effect of temozolomide in glioblastoma cells and a murine xenograft model

被引:8
作者
Fujihara, Toshitaka [1 ]
Mizobuchi, Yoshifumi [1 ]
Nakajima, Kohei [1 ]
Kageji, Teruyoshi [1 ]
Matsuzaki, Kazuhito [1 ]
Kitazato, Keiko T. [1 ]
Otsuka, Ryotaro [1 ]
Hara, Keijiro [1 ]
Mure, Hideo [1 ]
Okazaki, Toshiyuki [1 ]
Kuwayama, Kazuyuki [1 ]
Nagahiro, Shinji [1 ]
Takagi, Yasushi [1 ]
机构
[1] Tokushima Univ, Grad Sch, Dept Neurosurg, Inst Biomed Sci, 3-18-15 Kuramoto Cho, Tokushima 7708503, Japan
关键词
DKK3; MDR1; Akt; Glioblastoma; Temozolomide; P-GLYCOPROTEIN EXPRESSION; HUMAN BRAIN-TUMORS; MULTIDRUG-RESISTANCE; ADJUVANT TEMOZOLOMIDE; ENDOTHELIAL-CELLS; DRUG-RESISTANCE; GENE-EXPRESSION; SONIC-HEDGEHOG; BREAST-CANCER; GROWTH-FACTOR;
D O I
10.1007/s11060-018-2894-5
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Glioblastoma multiforme (GBM) is the most malignant of brain tumors. Acquired drug resistance is a major obstacle for successful treatment. Earlier studies reported that expression of the multiple drug resistance gene (MDR1) is regulated by YB-1 or NF kappa B via the JNK/c-Jun or Akt pathway. Over-expression of the Dickkopf (DKK) family member DKK3 by an adenovirus vector carrying DKK3 (Ad-DKK3) exerted anti-tumor effects and led to the activation of the JNK/c-Jun pathway. We investigated whether Ad-DKK3 augments the anti-tumor effect of temozolomide (TMZ) via the regulation of MDR1. GBM cells (U87MG and U251MG), primary TGB105 cells, and mice xenografted with U87MG cells were treated with Ad-DKK3 or TMZ alone or in combination. Ad-DKK3 augmentation of the anti-tumor effects of TMZ was associated with reduced MDR1 expression in both in vivo and in vitro studies. The survival of Ad-DKK3-treated U87MG cells was inhibited and the expression of MDR1 was reduced. This was associated with the inhibition of Akt/NF kappa B but not of YB-1 via the JNK/c-Jun- or Akt pathway. Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NF kappa B pathways and that it augments the anti-tumor effects of TMZ in GBM cells.
引用
收藏
页码:323 / 332
页数:10
相关论文
共 31 条
[1]   Adenovirus-mediated overexpression of REIC/Dkk-3 selectively induces apoptosis in human prostate cancer cells through activation of c-Jun-NH2-kinase [J].
Abarzua, F ;
Sakaguchi, M ;
Takaishi, M ;
Nasu, Y ;
Kurose, K ;
Ebara, S ;
Miyazaki, M ;
Namba, M ;
Kumon, H ;
Huh, N .
CANCER RESEARCH, 2005, 65 (21) :9617-9622
[2]   Tumor Endothelial Cells Acquire Drug Resistance by MDR1 Up-Regulation via VEGF Signaling in Tumor Microenvironment [J].
Akiyama, Kosuke ;
Ohga, Noritaka ;
Hida, Yasuhiro ;
Kawamoto, Taisuke ;
Sadamoto, Yoshihiro ;
Ishikawa, Shuhei ;
Maishi, Nako ;
Akino, Tomoshige ;
Kondoh, Miyako ;
Matsuda, Aya ;
Inoue, Nobuo ;
Shindoh, Masanobu ;
Hide, Kyoko .
AMERICAN JOURNAL OF PATHOLOGY, 2012, 180 (03) :1283-1293
[3]   Glioma stem cells promote radioresistance by preferential activation of the DNA damage response [J].
Bao, Shideng ;
Wu, Qiulian ;
McLendon, Roger E. ;
Hao, Yueling ;
Shi, Qing ;
Hjelmeland, Anita B. ;
Dewhirst, Mark W. ;
Bigner, Darell D. ;
Rich, Jeremy N. .
NATURE, 2006, 444 (7120) :756-760
[4]   Replication stress and oxidative damage contribute to aberrant constitutive activation of DNA damage signalling in human gliomas [J].
Bartkova, J. ;
Hamerlik, P. ;
Stockhausen, M-T ;
Ehrmann, J. ;
Hlobilkova, A. ;
Laursen, H. ;
Kalita, O. ;
Kolar, Z. ;
Poulsen, H. S. ;
Broholm, H. ;
Lukas, J. ;
Bartek, J. .
ONCOGENE, 2010, 29 (36) :5095-5102
[5]   P-glycoprotein Inhibition as a Therapeutic Approach for Overcoming Multidrug Resistance in Cancer: Current Status and Future Perspectives [J].
Binkhathlan, Ziyad ;
Lavasanifar, Afsaneh .
CURRENT CANCER DRUG TARGETS, 2013, 13 (03) :326-346
[6]   STRUCTURE AND EXPRESSION OF THE HUMAN MDR (P-GLYCOPROTEIN) GENE FAMILY [J].
CHIN, JE ;
SOFFIR, R ;
NOONAN, KE ;
CHOI, K ;
RONINSON, IB .
MOLECULAR AND CELLULAR BIOLOGY, 1989, 9 (09) :3808-3820
[7]  
CHOI YK, 2013, EVID-BASED COMPL ALT, DOI DOI 10.1155/2013/74198
[8]   Human brain tumors:: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells [J].
Fattori, Silvia ;
Becherini, Francesca ;
Cianfriglia, Maurizio ;
Parenti, Giuliano ;
Romanini, Antonella ;
Castagna, Maura .
VIRCHOWS ARCHIV, 2007, 451 (01) :81-87
[9]  
FINKELSTEIN SD, 1994, NEUROSURGERY, V34, P136
[10]   DNA Repair and Resistance of Gliomas to Chemotherapy and Radiotherapy [J].
Frosina, Guido .
MOLECULAR CANCER RESEARCH, 2009, 7 (07) :989-999