title: O-1602, an atypical cannabinoid, inhibits tumor growth in colitis-associated colon cancer through multiple mechanisms.
abstract: Cannabinoids have antiinflammatory and antitumorigenic properties. Some cannabinoids, such as O-1602, have no or only little affinity to classical cannabinoid receptors but exert cannabinoid-like antiinflammatory effects during experimental colitis. Here, we investigated whether O-1602 shows antitumorigenic effects in colon cancer cells and whether it could reduce tumorigenesis in the colon in vivo. The colon cancer cell lines HT-29 and SW480 were used to study the effect of O-1602 on viability and apoptosis. The effect of O-1602 on tumor growth in vivo was studied in a colitis-associated colon cancer mouse model. O-1602 decreased viability and induced apoptosis in colon cancer cells in a concentration-dependent manner (0.1-10 μM). In the mouse model, treatment with O-1602 (3 mg/kg, i.p., 12×) reduced tumor area by 50 % and tumor incidence by 30 %. Histological scoring revealed a significant decrease in tumor load. In tumor tissue, O-1602 decreased levels of proliferating cell nuclear antigen (PCNA), activation of oncogenic transcription factors STAT3 and NFκB p65, and expression of TNF-α while levels for proapoptotic markers, such as p53 and BAX, increased. The in vivo effects of O-1602 on PCNA, BAX, and p53 were also observed in colon cancer cells. The data provide a novel insight into antitumorigenic mechanisms of atypical cannabinoids. O-1602 exerts antitumorigenic effects by targeting colon cancer cells as well as proinflammatory pathways known to promote colitis-associated tumorigenesis. Due to its lack of central sedation, O-1602 could be an interesting compound for the treatment of colon and possibly other cancers.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010 Graz, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Kargl
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Angela
authors.initials: A
authors.lastname: Stančić
authors.forename: Liisa
authors.initials: L
authors.lastname: Andersen
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schicho
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002185:Cannabidiol / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000209:etiology*; D003510:Cyclohexanes / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D012118:Resorcinols / Q000008:administration & dosage / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003510:Cyclohexanes; D012118:Resorcinols; D050796:STAT3 Transcription Factor; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D002185:Cannabidiol; C568537:O-1602 compound