O-1602, an atypical cannabinoid, inhibits tumor growth in colitis-associated colon cancer through multiple mechanisms

• DOI: 10.1007/s00109-012-0957-1
• Publication Date: 2012-09-10T10:13:24Z
• Authors: Julia Kargl; Johannes Haybaeck; Angela Stančić; Liisa Andersen; Gunther Marsche; Akos Heinemann; Rudolf Schicho
• Keywords: Male; STAT3 Transcription Factor; 0301 basic medicine; Cell Survival; Tumor Necrosis Factor-alpha; Transcription Factor RelA; Apoptosis; Resorcinols; Colitis; Antineoplastic Agents, Phytogenic; Tumor Burden; 3. Good health; Disease Models, Animal; Mice; 03 medical and health sciences; Cyclohexanes; Cell Line, Tumor; Colonic Neoplasms; Animals; Cannabidiol; Humans; HT29 Cells; Cell Proliferation

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.