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

作者：Fujihara Toshitaka^*; Mizobuchi Yoshifumi; Nakajima Kohei; Kageji Teruyoshi; Matsuzaki Kazuhito; Kitazato Keiko T; Otsuka Ryotaro; Hara Keijiro; Mure Hideo; Okazaki Toshiyuki; Kuwayama Kazuyuki; Nagahiro Shinji; Takagi Yasushi

来源：Journal of Neuro-Oncology, 2018, 139(2): 323-332.

DOI：10.1007/s11060-018-2894-5

• DKK3
• MDR1
• Akt
• Glioblastoma
• Temozolomide

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.

• 出版日期2018-9