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
| Autor: | Yoshifumi Mizobuchi, Yasushi Takagi, Hideo Mure, Kazuhito Matsuzaki, Teruyoshi Kageji, Toshiyuki Okazaki, Ryotaro Otsuka, Keijiro Hara, Kazuyuki Kuwayama, Keiko T. Kitazato, Shinji Nagahiro, Kohei Nakajima, Toshitaka Fujihara |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Cancer Research Down-Regulation Drug resistance Viral vector Random Allocation 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation In vivo Cell Line Tumor Temozolomide medicine Animals Humans ATP Binding Cassette Transporter Subfamily B Member 1 Antineoplastic Agents Alkylating Protein kinase B PI3K/AKT/mTOR pathway Mice Inbred BALB C Brain Neoplasms Chemistry NF-kappa B Xenograft Model Antitumor Assays In vitro Gene Expression Regulation Neoplastic 030104 developmental biology Neurology Oncology 030220 oncology & carcinogenesis Cancer research Intercellular Signaling Peptides and Proteins Neurology (clinical) Glioblastoma Proto-Oncogene Proteins c-akt Signal Transduction medicine.drug |
| Zdroj: | Journal of Neuro-Oncology. 139:323-332 |
| ISSN: | 1573-7373 0167-594X |
| DOI: | 10.1007/s11060-018-2894-5 |
| Popis: | 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. 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/NFκB 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/NFκB pathways and that it augments the anti-tumor effects of TMZ in GBM cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink