Long term cannabinoid receptor (CB1) blockade in obesity: Implications for the development of colorectal cancer

Wright, Karen L.; Robertson, Douglas R.; Moyer, Mary Pat; Ward, Stephen G.

doi:10.1002/ijc.23304

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…Recent data have pointed out that the CB1 antagonist/inverse agonist AM251 is able to inhibit NCM460 cell proliferation 38. On the basis of this observation, obtained in cells exhibiting a nontransformed phenotype, the authors proposed that rimonabant might affect negatively the integrity and maintenance of the intestinal mucosa as a consequence of its continuous intake during the pharmacotherapy of obesity.…”

Section: Discussionmentioning

confidence: 99%

Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon

Santoro

Pisanti

Grimaldi

et al. 2009

Intl Journal of Cancer

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The selective CB1 receptor antagonist rimonabant (SR141716) was shown to perform a number of biological effects in several pathological conditions. Emerging findings demonstrate that rimonabant exerts antitumor action in thyroid tumors and breast cancer cells. In our study, human colorectal cancer cells (DLD-1, CaCo-2 and SW620) were treated with rimonabant and analyzed for markers of cell proliferation, cell viability and cell cycle progression. Rimonabant significantly reduced cell growth and induced cell death. In addition, rimonabant was able to alter cell cycle distribution in all the cell lines tested. Particularly, rimonabant produced a G2/M cell cycle arrest in DLD-1 cells without inducing apoptosis or necrosis. The G2/M phase arrest was characterized by a parallel enhancement of the number of mitoses associated to elevated DNA double strand breaks and chromosome misjoining events, hallmarks of mitotic catastrophe. Protein expression analyses of Cyclin B1, PARP-1, Aurora B and phosphorylated p38/MAPK and Chk1 demonstrated that rimonabantinduced mitotic catastrophe is mediated by interfering with the spindle assembly checkpoint and the DNA damage checkpoint. Moreover, in the mouse model of azoxymethane-induced colon carcinogenesis, rimonabant significantly decreased aberrant crypt foci (ACF) formation, which precedes colorectal cancer. Our findings suggest that rimonabant is able to inhibit colorectal cancer cell growth at different stages of colon cancer pathogenesis inducing mitotic catastrophe in vitro. ' UICCKey words: rimonabant; colon cancer; mitotic catastrophe; ACF formation Rimonabant (SR141716) is the first described highly selective antagonist for the cannabinoid receptor type 1 (CB1).1 Because of its ability to block the CB1 receptor, which controls food intake at central and peripheral level, rimonabant has been in clinical development for the treatment of obesity and its metabolic complications, including dyslipidemia, type 2 diabetes and atherosclerosis. However, rimonabant shows a plethora of pharmacological effects in a number of physiopathological conditions including cancer. 3The first observation of a rimonabant potential antitumor action was provided by our group in rat thyroid cancer cells (KiMol) in vitro and in thyroid tumor xenografts induced by KiMol injection in athymic mice. In this model, rimonabant was able to partially prevent the antitumor effect of endocannabinoid degradation inhibitors as well as of a metabolically stable analogue of the endocannabinoid anandamide (2-methylarachidonyl-2 0 -fluoroethylamide, Met-F-AEA). However, rimonabant, when used alone in the same model and at the dose able to counteract the Met-F-AEA effect, did not enhance tumor growth but instead it exerted a small, although significant, antitumor effect on thyroid tumors both in vitro and in vivo.4 Other authors demonstrated a potential antiproliferative effect of rimonabant: it decreased viability of primary mantle lymphoma cells isolated from tumor biopsies, 5 whilst a 48 hr incubation of C6 gl...

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Section: Discussionmentioning

confidence: 99%

Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon

Santoro

Pisanti

Grimaldi

et al. 2009

Intl Journal of Cancer

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“…Indeed the comorbidity of obesity and depression prompted a recent proposal to reclassify depressive syndromes as "metabolic syndrome type II" [118]. Other concerns with rimonabant or the RIO studies have surfaced [119][120][121][122].…”

Section: Clinical Concerns Regarding Systemic Cb 1 Blockade As a Treamentioning

confidence: 99%

Critical Role of the Endocannabinoid System in the Regulation of Food Intake and Energy Metabolism, with Phylogenetic, Developmental, and Pathophysiological Implications

Viveros

Fonseca²,

Bermúdez‐Silva³

et al. 2008

EMIDDT

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The endocannabinoid system (ECS) consists of two receptors (CB(1) and CB(2)), several endogenous ligands (primarily anandamide and 2-AG), and over a dozen ligand-metabolizing enzymes. The ECS has deep phylogenetic roots and regulates many aspects of embryological development and homeostasis, including neuroprotection and neural plasticity, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and the focus of this review: hunger, feeding, and metabolism. The ECS controls energy balance and lipid metabolism centrally (in the hypothalamus and mesolimbic pathways) and peripherally (in adipocytes and pancreatic islet cells), acting through numerous anorexigenic and orexigenic pathways (e.g., ghrelin, leptin, orexin, adiponectin, endogenous opioids, and corticotropin-releasing hormone). Obesity leads to excessive endocannabinoid production by adipocytes, which drives CB(1) in a feed-forward dysfunction. Phylogenetic research suggests the genes for endocannabinoid enzymes, especially DAGLalpha and NAPE-PLD, may harbor mildly deleterious alleles that express disease-related phenotypes. Several CB(1) inverse agonists have been developed for the treatment of obesity, including rimonabant, taranabant, and surinabant. These drugs are efficacious at reducing food intake as well as abdominal adiposity and cardiometabolic risk factors. However, given the myriad beneficial roles of the ECS, it should be no surprise that systemic CB(1) blockade induces various adverse effects. Alternatives to systemic blockade include CB(1) partial agonists, pleiotropic drugs, peripherally restricted antagonists, allosteric antagonists, and endocannabinoid ligand modulation. The ECS offers several discrete targets for the management of obesity and its associated cardiometabolic sequelae.

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“…In the recent letter by Wright et al, 1 it has been described that the cannabinoid receptor (CB1) antagonist/inverse agonist AM251 is able to inhibit NCM460 cell proliferation after a daily treatment of 96 hr. On the basis of this observation, obtained in cells exhibiting a nontransformed phenotype, the authors strongly suggest that rimonabant, another selective CB1 antagonist/inverse agonist, could affect negatively the integrity and maintenance of the intestinal mucosa as a consequence of its continuous intake during the pharmacotherapy of obesity.…”

Section: Dear Sirmentioning

confidence: 99%

Reply to the letter to the editor “Long‐term cannabinoid receptor (CB1) blockade in obesity: Implications for the development of colorectal cancer”

Gazzerro

Malfitano

Pisanti

et al. 2008

Intl Journal of Cancer

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Dear Sir,In the recent letter by Wright et al., 1 it has been described that the cannabinoid receptor (CB1) antagonist/inverse agonist AM251 is able to inhibit NCM460 cell proliferation after a daily treatment of 96 hr. On the basis of this observation, obtained in cells exhibiting a nontransformed phenotype, the authors strongly suggest that rimonabant, another selective CB1 antagonist/inverse agonist, could affect negatively the integrity and maintenance of the intestinal mucosa as a consequence of its continuous intake during the pharmacotherapy of obesity. They also suggest that rimonabant-induced mucosal damage might trigger persistent regenerative processes leading to colon cancer. From this point of view, we believe that the conclusions on rimonabant, obtained from experiments carried out with another CB1 antagonist/inverse agonist, could be hazardous, because rimonabant is really a highly selective CB1 receptor antagonist but it can also act in a way independent from the receptor. 2,3 We have just demonstrated that rimonabant exhibits immunomodulatory and antiinflammatory effects in normal human lymphocytes. 4 These effects were not associated to apoptosis but were characterized by a G1/S phase cell cycle arrest. In this system, rimonabant used in combination with the CB1 agonist anandamide showed synergistic/additive effect in the blockade of cell proliferation. 4 On the other hand, we have to taken into account that, even if both AM251 and rimonabant are able to block functionally the CB1 receptor, they are not the same molecule and this could be responsible for different kinds of biological responses evoked by the cells. Moreover, Izzo et al. 5 have recently demonstrated that the fatty acid amide hydrolase inhibitors increased colon endocannabinoid levels and reduced the formation of aberrant crypt foci (ACF) which are considered the earliest identifiable neoplastic lesions in humans. 6,7 Interestingly, no differences in ACF formation were observed between CB1 receptor-deficient and wild-type mice. It was concluded that pharmacological enhancement of endocannabinoid levels, through inhibition of endocannabinoid hydrolysis instead of CB1 modulation, reduces the development of precancerous lesions in the mouse colon. 5 Concerning colon cancer pathogenesis, we have interesting data that rimonabant significantly inhibits the viability of human adenocarcinoma DLD1 cells after 24 and 48 hr of treatment in a concentration-dependent manner (Fig. 1). Moreover, in colon mucosa, oestrogens and their receptors exert protective effects and the presence of considerable amounts of CB1 receptor, as well as oestrogen receptor expression has been shown in colorectal carcinoma and in human normal colon mucosa. 8 We have demonstrated that CB1 receptor is potentially an oestrogen-responsive gene in colon cancer cells DLD1 and SW620. In these cells, the oestrogen-mediated activation of CB1 receptor, at both transcriptional and posttranscriptional levels, suggests that oestrogen may modulate cancer cell growth via activatio...

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Long term cannabinoid receptor (CB1) blockade in obesity: Implications for the development of colorectal cancer

Cited by 4 publications

References 14 publications

Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon

Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon

Critical Role of the Endocannabinoid System in the Regulation of Food Intake and Energy Metabolism, with Phylogenetic, Developmental, and Pathophysiological Implications

Reply to the letter to the editor “Long‐term cannabinoid receptor (CB1) blockade in obesity: Implications for the development of colorectal cancer”

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