Document Detail


Morphine suppresses tumor angiogenesis through a HIF-1alpha/p38MAPK pathway.
MedLine Citation:
PMID:  20616349     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Morphine, a highly potent analgesic agent, is frequently prescribed for moderate to severe cancer pain. In this study, morphine was administered at a clinically relevant analgesic dose to assess tumor cell-induced angiogenesis and subcutaneous tumor growth in nude mice using mouse Lewis lung carcinoma cells (LLCs). Implantation of mice with a continuous slow-release morphine pellet achieved morphine plasma levels within 250-400 ng/ml (measured using a radioimmunoassay, Coat-A-Count Serum Morphine) and was sufficient to significantly reduce tumor cell-induced angiogenesis and tumor growth when compared with placebo treatment. Morphometric analysis for blood vessel formation further confirmed that morphine significantly reduced blood vessel density (P < 0.003), vessel branching (P < 0.05), and vessel length (P < 0.002) when compared with placebo treatment. Morphine's effect was abolished in mice coadministered the classical opioid receptor antagonist, naltrexone, and in mu-opioid receptor knockout mice, supporting the involvement of the classical opioid receptors in vivo. Morphine's inhibitory effect is mediated through the suppression of the hypoxia-induced mitochondrial p38 mitogen-activated protein kinase (MAPK) pathway. Our results suggest that in vitro morphine treatment of LLCs inhibits the hypoxia-induced nuclear translocation of hypoxia-inducible transcription factor 1alpha to reduce vascular endothelial growth factor transcription and secretion, in a manner similar to pharmacological blockade with the p38 MAPK-specific inhibitor, SB203585. These studies indicate that morphine, in addition to its analgesic function, may be exploited for its antiangiogenic potential.
Authors:
Lisa Koodie; Sundaram Ramakrishnan; Sabita Roy
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-07-08
Journal Detail:
Title:  The American journal of pathology     Volume:  177     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-03     Completed Date:  2011-01-25     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  984-97     Citation Subset:  AIM; IM    
Affiliation:
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
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MeSH Terms
Descriptor/Qualifier:
Analgesics, Opioid* / pharmacology,  therapeutic use
Animals
Anoxia / metabolism
Cell Line, Tumor
Enzyme Activation
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Lung Neoplasms / metabolism,  pathology
Mice
Mice, Knockout
Mice, Nude
Morphine* / pharmacology,  therapeutic use
Neoplasm Transplantation
Neovascularization, Pathologic* / drug therapy,  metabolism
Receptors, Opioid, mu / genetics,  metabolism
Signal Transduction / drug effects*
p38 Mitogen-Activated Protein Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
CA114340/CA/NCI NIH HHS; F31-DA021005-01/DA/NIDA NIH HHS; K02 DA015349-10/DA/NIDA NIH HHS; KO2 DA 015349/DA/NIDA NIH HHS; P50 DA 011806/DA/NIDA NIH HHS; R01 CA114340-05/CA/NCI NIH HHS; R01 DA 022935/DA/NIDA NIH HHS; R01 DA 12104/DA/NIDA NIH HHS; R01 DA012104-13/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Analgesics, Opioid; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Receptors, Opioid, mu; 57-27-2/Morphine; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases
Comments/Corrections

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