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

Abstract

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...

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

“…Also in this case, the effect was not due to apoptosis but was characterized by a cell cycle arrest 9. Moreover, in a preliminary study by our group, micromolar concentrations of rimonabant significantly inhibited the viability of human adenocarcinoma DLD‐1 cells after 24 and 48 hr of treatment in a concentration‐dependent manner 10…”

Rimonabant reduces keratinocyte viability by induction of apoptosis and exerts topical anti‐inflammatory activity in mice

“…It is widely used as a tool to investigate mechanisms by which cannabinoid agonists produce their pharmacological effects and may exert several of its actions by blocking the activation of CB1 receptors, thus modulating the endocannabinoid system, which is tonically activated under certain pathophysiological conditions (Di Marzo and Matias, 2005;Engeli et al, 2005;Matias et al, 2006;Jhaveri et al, 2007;Pertwee, 2009). Anti-tumour properties have been attributed to rimonabant by our group in several cancer cell lines in vitro and in vivo (Sarnataro et al, 2006;Santoro et al, 2008;2009;Gazzerro et al, 2010). Nonetheless, we very recently provided evidence that rimonabant increases human sperm motility and viability (Aquila et al, 2010).…”