title: Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde.
abstract: The progressive nature of colorectal cancer and poor prognosis associated with the metastatic phase of the disease create an urgent need for the development of more efficacious strategies targeting colorectal carcinogenesis. Cumulative evidence suggests that the redox-sensitive transcription factor Nrf2 (nuclear factor-E2-related factor 2), a master regulator of the cellular antioxidant defence, represents a promising molecular target for colorectal cancer chemoprevention. Recently, we have identified cinnamon, the ground bark of Cinnamomum aromaticum (cassia cinnamon) and Cinnamomum verum (Ceylon cinnamon), as a rich dietary source of the Nrf2 inducer cinnamaldehyde (CA) eliciting the Nrf2-regulated antioxidant response in human epithelial colon cells, conferring cytoprotection against electrophilic and genotoxic insult. Here, we have explored the molecular mechanism underlying CA-induced Nrf2 activation in colorectal epithelial cells and have examined the chemopreventive potential of CA in a murine colorectal cancer model comparing Nrf2(+/+) with Nrf2(-/-) mice. In HCT116 cells, CA caused a Keap1-C151-dependent increase in Nrf2 protein half-life via blockage of ubiquitination with upregulation of cytoprotective Nrf2 target genes and elevation of cellular glutathione. After optimizing colorectal Nrf2 activation and target gene expression by dietary CA-supplementation regimens, we demonstrated that CA suppresses AOM/DSS-induced inflammatory colon carcinogenesis with modulation of molecular markers of colorectal carcinogenesis. Dietary suppression of colorectal cancer using CA supplementation was achieved in Nrf2(+/+) but not in Nrf2(-/-) mice confirming the Nrf2 dependence of CA-induced chemopreventive effects. Taken together, our data suggest feasibility of colorectal cancer suppression by dietary CA, an FDA-approved food additive derived from the third most consumed spice in the world.
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona. Department of Endocrinology, Xinqiao Hospital, Third Military Medical University, Chongqing, P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona.
authors.forename: Shasha
authors.initials: S
authors.lastname: Tao
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Rojo de la Vega
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona. Department of Pharmacy, Jinan Central Hospital, Shandong University, Shandong, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Wen
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona.
authors.forename: Sophia L
authors.initials: SL
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona. wondrak@pharmacy.arizona.edu dzhang@pharmacy.arizona.edu.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy and Arizona Cancer Center, University of Arizona, Tucson, Arizona. wondrak@pharmacy.arizona.edu dzhang@pharmacy.arizona.edu.
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane; D063646:Carcinogenesis / Q000187:drug effects* / Q000235:genetics; D018890:Chemoprevention / Q000379:methods; D002935:Cinnamomum zeylanicum / Q000737:chemistry; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D016264:Dextran Sulfate; D004032:Diet; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*
chemical_list: D016588:Anticarcinogenic Agents; D051267:NF-E2-Related Factor 2; D000171:Acrolein; D016264:Dextran Sulfate; D001397:Azoxymethane; C012843:cinnamaldehyde