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Possible endocannabinoid control of colorectal cancer growth.

Abstract

BACKGROUND & AIMS

The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) inhibit cancer cell proliferation by acting at cannabinoid receptors (CBRs). We studied (1). the levels of endocannabinoids, cannabinoid CB(1) and CB(2) receptors, and fatty acid amide hydrolase (FAAH, which catalyzes endocannabinoid hydrolysis) in colorectal carcinomas (CRC), adenomatous polyps, and neighboring healthy mucosa; and (2). the effects of endocannabinoids, and of inhibitors of their inactivation, on human CRC cell proliferation.

METHODS

Tissues were obtained from 21 patients by biopsy during colonoscopy. Endocannabinoids were measured by liquid chromatography-mass spectrometry (LC-MS). CB(1), CB(2), and FAAH expression were analyzed by RT-PCR and Western immunoblotting. CRC cell lines (CaCo-2 and DLD-1) were used to test antiproliferative effects.

RESULTS

All tissues and cells analyzed contain anandamide, 2-AG, CBRs, and FAAH. The levels of the endocannabinoids are 3- and 2-fold higher in adenomas and CRCs than normal mucosa. Anandamide, 2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2 cell proliferation. This effect is blocked by the CB(1) antagonist SR141716A, but not by the CB(2) antagonist SR144528, and is mimicked by CB(1)-selective, but not CB(2)-selective, agonists. In DLD-1 cells, both CB(1) and CB(2) receptors mediate inhibition of proliferation. Inhibitors of endocannabinoid inactivation enhance CaCo-2 cell endocannabinoid levels and block cell proliferation, this effect being antagonized by SR141716A. CaCo-2 cell differentiation into noninvasive cells results in increased FAAH expression, lower endocannabinoid levels, and no responsiveness to cannabinoids.

CONCLUSIONS

Endocannabinoid levels are enhanced in transformed colon mucosa cells possibly to counteract proliferation via CBRs. Inhibitors of endocannabinoid inactivation may prove useful anticancer agents.

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  • Authors+Show Affiliations

    ,

    Endovannabinoid Research Group, Institute of Biomolecular Chemistry, Pozzuoli, Italy.

    , , , , , , , , ,

    Source

    Gastroenterology 125:3 2003 Sep pg 677-87

    MeSH

    Amidohydrolases
    Caco-2 Cells
    Cannabinoid Receptor Modulators
    Cell Differentiation
    Cell Division
    Colorectal Neoplasms
    Cyclooxygenase 2
    Endocannabinoids
    Fatty Acids, Unsaturated
    Humans
    Isoenzymes
    Membrane Proteins
    Prostaglandin-Endoperoxide Synthases
    Receptors, Cannabinoid
    Receptors, Drug

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    12949714

    Citation

    Ligresti, Alessia, et al. "Possible Endocannabinoid Control of Colorectal Cancer Growth." Gastroenterology, vol. 125, no. 3, 2003, pp. 677-87.
    Ligresti A, Bisogno T, Matias I, et al. Possible endocannabinoid control of colorectal cancer growth. Gastroenterology. 2003;125(3):677-87.
    Ligresti, A., Bisogno, T., Matias, I., De Petrocellis, L., Cascio, M. G., Cosenza, V., ... Di Marzo, V. (2003). Possible endocannabinoid control of colorectal cancer growth. Gastroenterology, 125(3), pp. 677-87.
    Ligresti A, et al. Possible Endocannabinoid Control of Colorectal Cancer Growth. Gastroenterology. 2003;125(3):677-87. PubMed PMID: 12949714.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Possible endocannabinoid control of colorectal cancer growth. AU - Ligresti,Alessia, AU - Bisogno,Tiziana, AU - Matias,Isabel, AU - De Petrocellis,Luciano, AU - Cascio,Maria Grazia, AU - Cosenza,Vittorio, AU - D'argenio,Giuseppe, AU - Scaglione,Giuseppe, AU - Bifulco,Maurizio, AU - Sorrentini,Italo, AU - Di Marzo,Vincenzo, PY - 2003/9/2/pubmed PY - 2003/10/3/medline PY - 2003/9/2/entrez SP - 677 EP - 87 JF - Gastroenterology JO - Gastroenterology VL - 125 IS - 3 N2 - BACKGROUND & AIMS: The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) inhibit cancer cell proliferation by acting at cannabinoid receptors (CBRs). We studied (1). the levels of endocannabinoids, cannabinoid CB(1) and CB(2) receptors, and fatty acid amide hydrolase (FAAH, which catalyzes endocannabinoid hydrolysis) in colorectal carcinomas (CRC), adenomatous polyps, and neighboring healthy mucosa; and (2). the effects of endocannabinoids, and of inhibitors of their inactivation, on human CRC cell proliferation. METHODS: Tissues were obtained from 21 patients by biopsy during colonoscopy. Endocannabinoids were measured by liquid chromatography-mass spectrometry (LC-MS). CB(1), CB(2), and FAAH expression were analyzed by RT-PCR and Western immunoblotting. CRC cell lines (CaCo-2 and DLD-1) were used to test antiproliferative effects. RESULTS: All tissues and cells analyzed contain anandamide, 2-AG, CBRs, and FAAH. The levels of the endocannabinoids are 3- and 2-fold higher in adenomas and CRCs than normal mucosa. Anandamide, 2-AG, and the CBR agonist HU-210 potently inhibit CaCo-2 cell proliferation. This effect is blocked by the CB(1) antagonist SR141716A, but not by the CB(2) antagonist SR144528, and is mimicked by CB(1)-selective, but not CB(2)-selective, agonists. In DLD-1 cells, both CB(1) and CB(2) receptors mediate inhibition of proliferation. Inhibitors of endocannabinoid inactivation enhance CaCo-2 cell endocannabinoid levels and block cell proliferation, this effect being antagonized by SR141716A. CaCo-2 cell differentiation into noninvasive cells results in increased FAAH expression, lower endocannabinoid levels, and no responsiveness to cannabinoids. CONCLUSIONS: Endocannabinoid levels are enhanced in transformed colon mucosa cells possibly to counteract proliferation via CBRs. Inhibitors of endocannabinoid inactivation may prove useful anticancer agents. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/12949714/Possible_endocannabinoid_control_of_colorectal_cancer_growth_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016508503008813 DB - PRIME DP - Unbound Medicine ER -