Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma

[img] PDF - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
1MB

Item Type:Article
Title:Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma
Creators Name:Friesen, C. and Hormann, I. and Roscher, M. and Fichtner, I. and Alt, A. and Hilger, R. and Debatin, K.M. and Miltner, E.
Abstract:Glioblastoma are the most frequent and malignant human brain tumors, having a very poor prognosis. The enhanced radio- and chemoresistance of glioblastoma and the glioblastoma stem cells might be the main reason why conventional therapies fail. The second messenger cyclic AMP (cAMP) controls cell proliferation, differentiation, and apoptosis. Downregulation of cAMP sensitizes tumor cells for anti-cancer treatment. Opioid receptor agonists triggering opioid receptors can activate inhibitory Gi proteins, which, in turn, block adenylyl cyclase activity reducing cAMP. In this study, we show that downregulation of cAMP by opioid receptor activation improves the effectiveness of anti-cancer drugs in treatment of glioblastoma. The µ-opioid receptor agonist D,L-methadone sensitizes glioblastoma as well as the untreatable glioblastoma stem cells for doxorubicin-induced apoptosis and activation of apoptosis pathways by reversing deficient caspase activation and deficient downregulation of XIAP and Bcl-xL, playing critical roles in glioblastomas' resistance. Blocking opioid receptors using the opioid receptor antagonist naloxone or increasing intracellular cAMP by 3-isobutyl-1-methylxanthine (IBMX) strongly reduced opioid receptor agonist-induced sensitization for doxorubicin. In addition, the opioid receptor agonist D,L-methadone increased doxorubicin uptake and decreased doxorubicin efflux, whereas doxorubicin increased opioid receptor expression in glioblastomas. Furthermore, opioid receptor activation using D,L-methadone inhibited tumor growth significantly in vivo. Our findings suggest that opioid receptor activation triggering downregulation of cAMP is a promising strategy to inhibit tumor growth and to improve the effectiveness of anti-cancer drugs in treatment of glioblastoma and in killing glioblastoma stem cells.
Keywords:Opioid Receptor, cAMP, D,L-Methadone, Chemoresistance, Glioblastoma, Glioblastoma Stem Cells, Chemotherapy, Apoptosis, Animals, Mice
Source:Cell Cycle
ISSN:1538-4101
Publisher:Landes Bioscience (U.S.A.)
Volume:13
Number:10
Page Range:1560-1570
Date:15 May 2014
Official Publication:https://doi.org/10.4161/cc.28493
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library