膠芽腫においてAd-DKK3の抗腫瘍効果はWnt蛋白と受容体の相互作用の阻害によりもたらされる

Field log book of Mike Gagner, labeled WM-7, 4/14/04, WM-7, 06/26/04, and WM-7, 8/20/04 of project 1418.01 PHABSIM site

膠芽腫細胞およびマウス背部皮下モデルにおいて，アデノウイルスベクターを用いたDKK3の導入はAkt/NFκB経路を介してMDR1の発現を抑制し，テモゾロミドによる抗腫瘍効果を増強する

Background: 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 NFκB 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. Methods: 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. Results: 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/NFκB but not of YB-1 via the JNK/c-Jun- or Akt pathway. Conclusions: Our results suggest that Ad-DKK3 regulates the expression of MDR1 via Akt/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells