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

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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.

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Acknowledgments

We would like to thank Veronika Pommer for excellent technical assistance. This study was supported by grants from the Austrian Science Fund (P 22771 to RS, P22521 to AH, and P21004 to GM), the Austrian National Bank (OeNB 14429 to RS and 14263 to AH), the Franz Lanyar Foundation (351 to RS), and the Innovative Medicines Initiative Joint Undertaking (IMI) Grant (OncoTrack to JH). JK and AS are funded by the PhD program of the Medical University of Graz.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria

    Julia Kargl, Angela Stančić, Liisa Andersen, Gunther Marsche, Akos Heinemann & Rudolf Schicho

  2. Institute of Pathology, Medical University of Graz, Graz, Austria

    Johannes Haybaeck

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  1. Julia Kargl
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Correspondence to Rudolf Schicho.

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Kargl, J., Haybaeck, J., Stančić, A. et al. O-1602, an atypical cannabinoid, inhibits tumor growth in colitis-associated colon cancer through multiple mechanisms. J Mol Med 91, 449–458 (2013). https://doi.org/10.1007/s00109-012-0957-1

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  • DOI: https://doi.org/10.1007/s00109-012-0957-1

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