R(+)-Methanandamide Elicits a Cyclooxygenase-2-Dependent Mitochondrial Apoptosis Signaling Pathway in Human Neuroglioma Cells

doi:10.1007/s11095-005-8815-2

Paper

R(+)-Methanandamide Elicits a Cyclooxygenase-2-Dependent Mitochondrial Apoptosis Signaling Pathway in Human Neuroglioma Cells

Published Nov 8, 2006 · K. Eichele, U. Weinzierl, R. Ramer

Pharmaceutical Research

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Abstract

PurposeCannabinoids have been associated with tumor regression and apoptosis of cancer cells. Recently, we have shown that R(+)-methanandamide (R(+)-MA) induces apoptosis of H4 human neuroglioma cells via a mechanism involving de novo expression of the cyclooxygenase-2 (COX-2) enzyme. The present study investigated a possible involvement of a mitochondrial-driven pathway in this process.MethodsCell death was determined by the WST-1 cell viability test, and changes in apoptotic parameters [i.e., release of mitochondrial cytochrome c, activation of caspases, cleavage of poly(ADP-ribose) polymerase (PARP)] were detected by Western blotting.ResultsH4 cells treated with R(+)-MA showed typical signs of mitochondrial apoptosis, i.e., release of mitochondrial cytochrome c into the cytosol and activation of initiator caspase-9. Moreover, activation of the executor caspase-3 was observed following cannabinoid treatment. Cells were fully protected from apoptotic cell death by the caspase-3 inhibitor Ac-DEVD-CHO, indicating a crucial role for caspase-3 activation in R(+)-MA-elicited apoptosis. Furthermore, cleavage of the caspase-3 target protein PARP was registered. All of the aforementioned effects were substantially reduced by the selective COX-2 inhibitor celecoxib (1 μM) at a pharmacologically relevant, nonapoptotic concentration.ConclusionR(+)-MA-induced apoptosis is mediated via a mitochondrial-dependent pathway that becomes activated, at least in part, through up-regulation of the COX-2 enzyme.

In Vitro Study

Study Snapshot

R(+)-methanandamide induces apoptosis in human neuroglioma cells through a mitochondrial-dependent pathway, partially activated by up-regulation of the COX-2 enzyme.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

R(+)-Methanandamide Elicits a Cyclooxygenase-2-Dependent Mitochondrial Apoptosis Signaling Pathway in Human Neuroglioma Cells

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References

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Up-Regulation of Cyclooxygenase-2 Expression Is Involved in R(+)-Methanandamide-Induced Apoptotic Death of Human Neuroglioma Cells

Cannabinoid R(+)-methanandamide induces apoptosis in human neuroglioma cells, and COX-2 inhibitors may diminish this effect, suggesting potential for glioma regression.

Involvement of ERK1/2 and p38 MAP Kinase in Doxorubicin-Induced uPA Expression in Human RC-K8 Lymphoma and NCI-H69 Small Cell Lung Carcinoma Cells

Doxorubicin-induced uPA expression in human RC-K8 lymphoma and NCI-H69 small cell lung carcinoma cells involves different MAP kinase signaling, and manipulating this signaling could potentially alter tumor cell biology.

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The endocannabinoid system has evolved to include more endogenous substances and molecular targets, expanding our understanding of its biochemistry and pharmacology.

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