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

Author(s)

Vendramini-Costa, Debora Barbosa ; Francescone, Ralph ; Posocco, David ; Hou, Vivianty ; Dmitrieva, Oxana ; Hensley, Harvey ; de Carvalho, Joao Ernesto ; Pilli, Ronaldo Aloise ; Grivennikov, Sergei I.

• Document type: Journal article
• Source: Carcinogenesis; v. 38, n. 1, p. 51-63, JAN 2017.
• Web of Science Citations: 10

Abstract

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 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), 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-alpha in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-kappa B. 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-alpha 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. (AU)

• FAPESP's process: 09/51602-5 - Chemical biology: new natural and synthetic molecular targets against cancer, structural studies, biological evaluation and mode of action
• Grantee: Ronaldo Aloise Pilli
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 14/05189-7 - Evaluation of the preventive and therapeutic potential of goniothalamin in colitis associated colon cancer and in sporadic colon cancer models
• Grantee: Débora Barbosa Vendramini Costa
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor