Abstract
Colorectal cancer (CRC) is a major cause of tumor-related morbidity and mortality worldwide. Recent research suggests that pharmacological intervention using dietary factors that activate the redox sensitive Nrf2/Keap1-ARE signaling pathway may represent a promising strategy for chemoprevention of human cancer including CRC. In our search for dietary Nrf2 activators with potential chemopreventive activity targeting CRC, we have focused our studies on trans-cinnamic aldehyde (cinnamaldeyde, CA), the key flavor compound in cinnamon essential oil. Here we demonstrate that CA and an ethanolic extract (CE) prepared from Cinnamomum cassia bark, standardized for CA content by GC-MS analysis, display equipotent activity as inducers of Nrf2 transcriptional activity. In human colon cancer cells (HCT116, HT29) and non-immortalized primary fetal colon cells (FHC), CA- and CE-treatment upregulated cellular protein levels of Nrf2 and established Nrf2 targets involved in the antioxidant response including heme oxygenase 1 (HO-1) and γ-glutamyl-cysteine synthetase (γ-GCS, catalytic subunit). CA- and CE-pretreatment strongly upregulated cellular glutathione levels and protected HCT116 cells against hydrogen peroxide-induced genotoxicity and arsenic-induced oxidative insult. Taken together our data demonstrate that the cinnamon-derived food factor CA is a potent activator of the Nrf2-orchestrated antioxidant response in cultured human epithelial colon cells. CA may therefore represent an underappreciated chemopreventive dietary factor targeting colorectal carcinogenesis.
Highlights
Colorectal cancer (CRC) is a major cause of tumor-related morbidity and mortality worldwide [1,2].Progression of CRC can occur over decades and involves the early development of adenomatous precursor lesions followed by invasive stages of the disease [3]
In our search for promising dietary NF-E2related factor 2 (Nrf2) activators with potential chemopreventive activity targeting CRC we have focused our studies on trans-cinnamic aldehyde, the key flavor compound in cinnamon essential oil extracted from Cinnamomum zeylanicum and Cinnamomum cassia bark
We have shown that cinnamic aldehyde (CA), the major volatile constituent contained in cinnamon powder, is a potent inducer of Nrf2 transcriptional activity in cultured human epithelial and dermal skin cells [17]
Summary
Colorectal cancer (CRC) is a major cause of tumor-related morbidity and mortality worldwide [1,2]. Recent research suggests that pharmacological intervention using dietary factors that activate the redox sensitive Nrf2/Keap1-ARE signaling pathway may represent a promising strategy for chemoprevention of human cancer including CRC [7,8,9]. In our search for promising dietary Nrf activators with potential chemopreventive activity targeting CRC we have focused our studies on trans-cinnamic aldehyde (cinnamaldehyde, CA), the. -unsaturated aldehyde CA is a reactive Michael acceptor that spontaneously forms covalent adducts with model thiols and activates Nrf2-regulated antioxidant response element (ARE)-mediated gene expression [17]. We demonstrate that CA and an ethanolic cinnamon extract with standardized CA content (CE) display potent activity as activators of Nrf transcriptional activity, Nrf protein upregulation, and Nrf target gene expression in human colon cancer and fetal colon cells. CA and an ethanolic cinnamon extract induce the antioxidant defense in colon epithelial cells and elevate cellular glutathione levels resulting in increased resistance to oxidative insult from arsenic and hydrogen peroxide
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