Diverse nutritional phytochemicals are powerful medicinal products in promoting human health and diseases prevention including cancer. These dietary “antioxidants” can trap reactive species RONS, trigger cellular signaling events including “proteins thiol modifications” leading to expression of cellular defense and other genes. Our lab study dietary phenolic-antioxidants, isothiocyanates, tocopherols, omega-3 fatty acids and herbal medicines, which are effective against many animal carcinogenesis models. These compounds modulate kinases, activate Nrf2-mediated antioxidative stress/anti-inflammatory pathways and induce cellular defense genes HO-1, GST, and NQO1. Integrating Nrf2-/- mice with microarray bioinformatics, other genes including apoptosis, cell adhesion, cell growth, kinases, electron transport, transcription factors, and ubiquitination, are also Nrf2 targets, leading to the overall cellular protective effects against oxidative/carcinogenic damages, particularly during carcinogenesis initiation. The Nrf2-/- mice are more prone to carcinogen-induced skin, colon and other cancers and are more susceptible to DSS-induced colon inflammation and DSS-AOM-induced colon carcinogenesis. Inhibition of LPS-induced inflammation in mouse macrophages by sulforaphane (SFN) would require Nrf2. Epigenetically, in the prostate TRAMP tumors, as cancer progresses, a shut-down of Nrf2 via CpG methylation of the promoter region, attenuating Nrf2-mediated genes, which were reversed by dietary PEITC, curcumin and tocopherols. Curcumin could demethylate CpGs of Nrf2 promoter in TRAMP C1 cells and Neurog1 promoter in LNCaP cells, which would impact early carcinogenesis and later stages of cancer development. Hence, nutritional phytochemicals can confer early chemopreventive epigenetic effects resulting in blocking initiation/promotion of carcinogenesis, as well as late stage of epigenetic effects inhibiting progression of carcinogenesis. Supported by NIH grants .
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