title: Anti-inflammatory natural product goniothalamin reduces colitis-associated and sporadic colorectal tumorigenesis.
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 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.
authors: Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.|Institute of Chemistry, University of Campinas, Campinas, São Paulo 13083-970, Brazil.|Present address: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors: Débora Barbosa
authors: DB
authors: Vendramini-Costa
authors: Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors: Ralph
authors: R
authors: Francescone
authors: Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors: David
authors: D
authors: Posocco
authors: Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors: Vivianty
authors: V
authors: Hou
authors: Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA.
authors: Oxana
authors: O
authors: Dmitrieva
authors: Biological Imaging Facility, Fox Chase Cancer Center, Philadelphia, PA 19111, USA and.
authors: Harvey
authors: H
authors: Hensley
authors: Faculty of Pharmaceutical Sciences, University of Campinas, Campinas, São Paulo 13083-970, Brazil.
authors: João Ernesto
authors: JE
authors: de Carvalho
authors: Institute of Chemistry, University of Campinas, Campinas, São Paulo 13083-970, Brazil.
authors: Ronaldo Aloise
authors: RA
authors: Pilli
authors: Cancer Prevention and Control Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA, sergey.grivennikov@fccc.edu.
authors: Sergei I
authors: SI
authors: Grivennikov
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001397:Azoxymethane / Q000633:toxicity; D001688:Biological Products / Q000494:pharmacology; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000150:complications*; D015179:Colorectal Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000150:complications; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D011753:Pyrones / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D001688:Biological Products; D002273:Carcinogens; D016207:Cytokines; D018836:Inflammation Mediators; D011753:Pyrones; C103280:goniothalamin; D016264:Dextran Sulfate; D001397:Azoxymethane