Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis

• Published in: Carcinogenesis (New York) Vol. 38; no. 1; pp. 51 - 63
• Main Authors: Vendramini-Costa, Débora Barbosa, Francescone, Ralph, Posocco, David, Hou, Vivianty, Dmitrieva, Oxana, Hensley, Harvey, de Carvalho, João Ernesto, Pilli, Ronaldo Aloise, Grivennikov, Sergei I
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.01.2017
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Azoxymethane - toxicity; Biological Products - pharmacology; Carcinogens - toxicity; Cell Transformation, Neoplastic - drug effects; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Cells, Cultured; Colitis - chemically induced; Colitis - complications; Colorectal Neoplasms - etiology; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Colorectal Neoplasms - prevention & control; Cytokines - antagonists & inhibitors; Cytokines - genetics; Cytokines - metabolism; Dextran Sulfate - toxicity; Inflammation - chemically induced; Inflammation - complications; Inflammation Mediators - antagonists & inhibitors; Inflammation Mediators - metabolism; Macrophages - drug effects; Macrophages - metabolism; Macrophages - pathology; Mice; Mice, Inbred C57BL; Original Manuscript; Pyrones - pharmacology
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgw112

The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities. Because inflammation is a major driver of colorectal cancer (CRC), we therefore evaluated the therapeutic and preventive potentials of GTN in colitis, colitis-associated cancer (CAC) and spontaneous CRC. First, in a simplistic model of inflammation in vitro, GTN was able to inhibit cytokine production in bone marrow-derived macrophages induced by lipopolysaccharide. Next, in dextran sulfate sodium (DSS) induced-colitis model, mice treated with GTN displayed restored tissue architecture, increased cell proliferation in the colonic crypts and reduced epithelial damage. Moreover, colon tissue from GTN-treated mice had significantly less expression of the inflammatory genes interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), S100A9, interleukin 23A (IL-23A), IL-22 and IL-17A In the azoxymethane/DSS model of CAC, GTN reduced tumor multiplicity, load and size. Additionally, GTN suppressed production of IL-6, IL-17 and TNF-α in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-κB. Finally, in a tamoxifen inducible model of sporadic CRC, GTN-treated mice had significantly fewer tumors and decreased levels of IL-17A, IL-6, S100A9 and TNF-α protein within the tumors. These results suggest that GTN possesses anti-inflammatory and antitumor activities and represents a preventive and therapeutic agent modulating the inflammatory environment in the colon during colitis as well as CAC and CRC development.