Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon.
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 rimonabant-induced 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.
Santoro
Antonietta
A
Department of Pharmaceutical Sciences, University of Salerno, Fisciano, Italy.
Pisanti
Simona
S
Grimaldi
Claudia
C
Izzo
Angelo A
AA
Borrelli
Francesca
F
Proto
Maria C
MC
Malfitano
Anna M
AM
Gazzerro
Patrizia
P
Laezza
Chiara
C
Bifulco
Maurizio
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D063387:Cannabinoid Receptor Antagonists; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D000071877:Checkpoint Kinase 1; D002869:Chromosome Aberrations; D003114:Colony-Forming Units Assay; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008940:Mitotic Index; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011123:Polyploidy; D011230:Precancerous Conditions / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000627:therapeutic use*; D000077285:Rimonabant; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C534699:CCNB1 protein, human; D063387:Cannabinoid Receptor Antagonists; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D010880:Piperidines; D011720:Pyrazoles; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D011494:Protein Kinases; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001397:Azoxymethane; D000077285:Rimonabant