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

Abstract

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...

PAX3-FOXO1 Induces Cannabinoid Receptor 1 to Enhance Cell Invasion and Metastasis

“…In thyroid, breast, glioma, and prostate cancer cells, Cnr1 agonists inhibited proliferation which could be abrogated by antagonists (18,(41)(42)(43). Moreover, conflicting results have been obtained in colorectal cancer where Cnr1 agonists can induce apoptosis and inhibit growth, whereas antagonist treatment can either accelerate or prevent precancerous lesion formation, depending on the animal model used (37,44,45). However, we could find no contribution of Cnr1 to PAX3-FOXO1-induced myoblast growth.…”

Human Sperm Anatomy: Ultrastructural Localization of the Cannabinoid1 Receptor and a Potential Role of Anandamide in Sperm Survival and Acrosome Reaction

“…It is likely that the efficacy for the production of inverse cannabimimetic effects will be governed by the degree of ongoing endocannabinoid release onto CB1 receptors. Therefore, we could also hypothesize that SR1, by acting as an inverse agonist is able to enhance MET-F-AEA effects as already proposed in other experimental system by our group (Esposito et al, 2008;Santoro et al, 2009).…”

Genetic and pharmacologic inactivation of cannabinoid CB1 receptor inhibits angiogenesis

“…Blocking CB1 signaling has been reported to inhibit tumor growth in thyroid, mantle-cell lymphoma, and breast and colon tumors both in vitro and in vivo. [19][20][21][22] Angiogenesis, the de novo development of blood vessels, occurs regularly in adult tissues in physiologic and pathologic conditions, including wound healing, inflammation, rheumatoid arthritis, endometriosis, diabetic retinopathy, macular degeneration, and tumor progression. [23][24][25] Several complex steps are involved, the first one represented by localized enzymatic degradation of the basement membrane of the existing vessels, followed by the detachment of endothelial cells from adhesive proteins in the extracellular matrix and migration into the perivascular space, where cells proliferate.…”