Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma
- PMID: 16936228
- DOI: 10.1124/mol.106.025981
Cannabinoid receptor-mediated apoptosis induced by R(+)-methanandamide and Win55,212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma
Abstract
We have recently shown that cannabinoids induce growth inhibition and apoptosis in mantle cell lymphoma (MCL), a malignant B-cell lymphoma that expresses high levels of cannabinoid receptor types 1 and 2 (CB(1) and CB(2)). In the current study, the role of each receptor and the signal transduction triggered by receptor ligation were investigated. Induction of apoptosis after treatment with the synthetic agonists R(+)-methanandamide [R(+)-MA] and Win55,212-2 (Win55; (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone) was dependent on both cannabinoid receptors, because pretreatment with N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and N-((1S)-endo-1,3,3-trimethyl bicyclo heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide) (SR144528), specific antagonists to CB(1) and CB(2), respectively, abrogated caspase-3 activity. Preincubation with the inhibitors 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and 4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190) showed that phosphorylation of MAPK p38 was implicated in the signal transduction leading to apoptosis. Treatment with R(+)-MA and Win55 was associated with accumulation of ceramide, and pharmacological inhibition of ceramide synthesis de novo prevented both p38 activation and mitochondria depolarization assessed by binding of 3,3'-dihexyloxacarbocyanine iodide (DiOC(6)). In contrast, the pancaspase inhibitor z-Val-Ala-Asp(Ome)-CH(2)F (z-VAD-FMK) did not protect the mitochondrial integrity. Taken together, these results suggest that concurrent ligation of CB(1) and CB(2) with either R(+)-MA or Win55 induces apoptosis via a sequence of events in MCL cells: accumulation of ceramide, phosphorylation of p38, depolarization of the mitochondrial membrane, and caspase activation. Although induction of apoptosis was observed in both MCL cell lines and primary MCL, normal B cells remained unaffected. The present data suggest that targeting CB(1)/CB(2) may have therapeutic potential for the treatment of mantle cell lymphoma.
Similar articles
-
Anandamide-mediated CB1/CB2 cannabinoid receptor--independent nitric oxide production in rabbit aortic endothelial cells.J Pharmacol Exp Ther. 2007 Jun;321(3):930-7. doi: 10.1124/jpet.106.117549. Epub 2007 Mar 22. J Pharmacol Exp Ther. 2007. PMID: 17379772
-
Pharmacological characterisation of cannabinoid receptors inhibiting interleukin 2 release from human peripheral blood mononuclear cells.Eur J Pharmacol. 2003 Mar 19;464(2-3):207-15. doi: 10.1016/s0014-2999(03)01379-7. Eur J Pharmacol. 2003. PMID: 12620515
-
Inhibition of interleukin-8 release in the human colonic epithelial cell line HT-29 by cannabinoids.Eur J Pharmacol. 2003 Jan 1;458(1-2):207-15. doi: 10.1016/s0014-2999(02)02698-5. Eur J Pharmacol. 2003. PMID: 12498928
-
Characterization of cannabinoid modulation of sensory neurotransmission in the rat isolated mesenteric arterial bed.J Pharmacol Exp Ther. 2004 Oct;311(1):411-9. doi: 10.1124/jpet.104.067587. Epub 2004 Jun 17. J Pharmacol Exp Ther. 2004. PMID: 15205450
-
CB1 receptors in the preoptic anterior hypothalamus regulate WIN 55212-2 [(4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia.J Pharmacol Exp Ther. 2002 Jun;301(3):963-8. doi: 10.1124/jpet.301.3.963. J Pharmacol Exp Ther. 2002. PMID: 12023525
Cited by
-
Effects of Cannabidiol, ∆9-Tetrahydrocannabinol, and WIN 55-212-22 on the Viability of Canine and Human Non-Hodgkin Lymphoma Cell Lines.Biomolecules. 2024 Apr 19;14(4):495. doi: 10.3390/biom14040495. Biomolecules. 2024. PMID: 38672512 Free PMC article.
-
Sphingolipids and Lymphomas: A Double-Edged Sword.Cancers (Basel). 2022 Apr 19;14(9):2051. doi: 10.3390/cancers14092051. Cancers (Basel). 2022. PMID: 35565181 Free PMC article. Review.
-
Expression and Functions of the CB2 Receptor in Human Leukocytes.Front Pharmacol. 2022 Feb 22;13:826400. doi: 10.3389/fphar.2022.826400. eCollection 2022. Front Pharmacol. 2022. PMID: 35273503 Free PMC article.
-
Targeting the Endocannabinoid System: From the Need for New Therapies to the Development of a Promising Strategy. What About Pancreatic Cancer?In Vivo. 2022 Mar-Apr;36(2):543-555. doi: 10.21873/invivo.12736. In Vivo. 2022. PMID: 35241505 Free PMC article. Review.
-
Cannabis, a Miracle Drug with Polyvalent Therapeutic Utility: Preclinical and Clinical-Based Evidence.Med Cannabis Cannabinoids. 2021 May 21;4(1):43-60. doi: 10.1159/000515042. eCollection 2021 Jun. Med Cannabis Cannabinoids. 2021. PMID: 34676349 Free PMC article. Review.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Medical
Research Materials