Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells.

Cianchi F1Papucci LSchiavone NLulli MMagnelli LVinci MCMesserini LManera CRonconi ERomagnani PDonnini MPerigli GTrallori GTanganelli ECapaccioli SMasini E.

Abstract

PURPOSE:

Cannabinoids have been recently proposed as a new family of potential antitumor agents. The present study was undertaken to investigate the expression of the two cannabinoid receptors, CB1 and CB2, in colorectal cancer and to provide new insight into the molecular pathways underlying the apoptotic activity induced by their activation.

EXPERIMENTAL DESIGN:

Cannabinoid receptor expression was investigated in both human cancer specimens and in the DLD-1 and HT29 colon cancer cell lines. The effects of the CB1 agonist arachinodyl-2′-chloroethylamide and the CB2 agonist N-cyclopentyl-7-methyl-1-(2-morpholin-4-ylethyl)-1,8-naphthyridin-4(1H)-on-3-carboxamide (CB13) on tumor cell apoptosis and ceramide and tumor necrosis factor (TNF)-alpha production were evaluated. The knockdown of TNF-alpha mRNA was obtained with the use of selective small interfering RNA.

RESULTS:

We show that the CB1 receptor was mainly expressed in human normal colonic epithelium whereas tumor tissue was strongly positive for the CB2 receptor. The activation of the CB1 and, more efficiently, of the CB2 receptors induced apoptosis and increased ceramide levels in the DLD-1 and HT29 cells. Apoptosis was prevented by the pharmacologic inhibition of ceramide de novo synthesis. The CB2 agonist CB13 also reduced the growth of DLD-1 cells in a mouse model of colon cancer. The knockdown of TNF-alpha mRNA abrogated the ceramide increase and, therefore, the apoptotic effect induced by cannabinoid receptor activation.

CONCLUSIONS:

The present study shows that either CB1 or CB2 receptor activation induces apoptosis through ceramide de novo synthesis in colon cancer cells. Our data unveiled, for the first time, that TNF-alpha acts as a link between cannabinoid receptor activation and ceramide production.

Artículo completo: https://www.ncbi.nlm.nih.gov/pubmed/19047095

ARTICULOS

cannabis de esperanza

Naciones Unidas trabaja en facilitar “la investigación y comercio de cannabis mundial” (FAAAT Carta Abierta)

La primera publicidad educativa cannábica aprobada en Londres (TRADUCCIÓN)

Cannabis medicinal: reglamento del Minsa aún margina a pacientes (LA ENTREVISTA)

Perú: Convenio Dará Cannabis Medicinal Sin Costo a Pacientes de Bajos Recursos

Encuesta Federal Identifica Notorio Decrecimiento en El Uso de Marihuana en Gente Joven (TRADUCCIÓN)

LA ONU Y LA OMS CIERRAN 60 AÑOS DE PARÉNTESIS OSCURANTISTA (PARTE 1)

VIDEOS

Cannabis Medicinal y Fibromialgia: El Camino de Libertad

El científico (The Scientist – subtitulos en español)

Primera Charla Gratuita Cannabis Medicinal, Dr. Dave Hepburn MD

Cannabis Medicinal y Fibromialgia: El Camino de Libertad

El científico (The Scientist – subtitulos en español)

Primera Charla Gratuita Cannabis Medicinal, Dr. Dave Hepburn MD

Open chat