R(+)-methanandamide-induced apoptosis of human cervical carcinoma cells involves a cyclooxygenase-2-dependent pathway.

Abstract

PURPOSE:

Cannabinoids have received renewed interest due to their antitumorigenic effects. Using human cervical carcinoma cells (HeLa), this study investigates the role of cyclooxygenase-2 (COX-2) in apoptosis elicited by the endocannabinoid analog R(+)-methanandamide (MA).

METHODS:

COX-2 expression was assessed by RT-PCR and Western blotting. PGE2/PGD2 levels in cell culture supernatants and DNA fragmentation were measured by ELISA.

RESULTS:

MA led to an induction of COX-2 expression, PGD2 and PGE2 synthesis. Cells were significantly less sensitive to MA-induced apoptosis when COX-2 was suppressed by siRNA or the selective COX-2 inhibitor NS-398. COX-2 expression and apoptosis by MA was also prevented by the ceramide synthase inhibitor fumonisin B1, but not by antagonists to cannabinoid receptors and TRPV1. In line with the established role of peroxisome proliferator-activated receptor gamma (PPARgamma) in the proapoptotic action of PGs of the D and J series, inhibition of MA-induced apoptosis was also achieved by siRNA targeting lipocalin-type PGD synthase (L-PGDS) or PPARgamma. A role of COX-2 and PPARgamma in MA-induced apoptosis was confirmed in another human cervical cancer cell line (C33A) and in human lung carcinoma cells (A549).

CONCLUSION:

This study demonstrates COX-2 induction and synthesis of L-PGDS-derived, PPARgamma-activating PGs as a possible mechanism of apoptosis by MA.

• Authors: Karin Eichele, Robert Ramer, Burkhard Hinz
• Journal: Pharmaceutical research (Pharm Res) Vol. 26 Issue 2 Pg. 346-55 (Feb 2009) ISSN: 0724-8741 [Print] United States
• PMID: 19015962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Arachidonic Acids
• Cyclooxygenase 2 Inhibitors
• Fumonisins
• Lipocalins
• Nitrobenzenes
• PPAR gamma
• RNA, Messenger
• RNA, Small Interfering
• Sulfonamides
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• methanandamide
• fumonisin B1
• Oxidoreductases
• Cyclooxygenase 2
• PTGS2 protein, human
• dihydroceramide desaturase
• Intramolecular Oxidoreductases
• prostaglandin R2 D-isomerase
• Dinoprostone
• Prostaglandin D2

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Arachidonic Acids (pharmacology)
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• DNA Fragmentation
• Dinoprostone (metabolism)
• Dose-Response Relationship, Drug
• Female
• Fumonisins (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• HeLa Cells
• Humans
• Intramolecular Oxidoreductases (metabolism)
• Lipocalins (metabolism)
• Nitrobenzenes (pharmacology)
• Oxidoreductases (antagonists & inhibitors, metabolism)
• PPAR gamma (metabolism)
• Prostaglandin D2 (metabolism)
• RNA Interference
• RNA, Messenger (metabolism)
• RNA, Small Interfering (metabolism)
• Sulfonamides (pharmacology)
• Time Factors
• Uterine Cervical Neoplasms (enzymology, genetics, pathology)