title: A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways.
abstract: Natural compounds containing vanilloid and Michael acceptor moieties appear to possess anti-cancer and chemopreventive properties. The ginger constituent shogaol represents one such compound. In this study, the anti-cancer potential of a synthetic novel shogaol analog 3-phenyl-3-shogaol (3-Ph-3-SG) was assessed by evaluating its effects on signaling pathways. At non-toxic concentrations, 3-Ph-3-SG suppressed cancer cell invasion in MDA-MB-231 and MCF-7 breast carcinoma cells through inhibition of PMA-activated MMP-9 expression. At similar concentrations, 3-Ph-3-SG reduced expression of the inflammatory mediators nitric oxide (NO), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and prostanglandin-E2 (PGE2) in RAW 264.7 macrophage-like cells. Inhibition of cancer cell invasion and inflammation by 3-Ph-3-SG were mediated through suppression of the nuclear factor-kappaB (NF-κB) signaling pathway. The 3-Ph-3-SG also demonstrated cytoprotective effects by inducing the antioxidant response element (ARE)-driven genes NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HO-1). Cytoprotection by 3-Ph-3-SG was achieved at least partly through modification of cysteine residues in the E3 ubiquitin ligase substrate adaptor Kelch-like ECH-associated protein 1 (Keap1), which resulted in accumulation of transcription factor NF-E2 p45-related factor 2 (Nrf2). The activities of 3-Ph-3-SG were comparable to those of 6-shogaol, the most abundant naturally-occurring shogaol, and stronger than those of 4-hydroxyl-null deshydroxy-3-phenyl-3-shogaol, which attested the importance of the 4-hydroxy substituent in the vanilloid moiety for bioactivity. In summary, 3-Ph-3-SG is shown to possess activities that modulate stress-associated pathways relevant to multiple steps in carcinogenesis. Therefore, it warrants further investigation of this compound as a promising candidate for use in chemotherapeutic and chemopreventive strategies.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, Republic of Singapore.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Gan
authors.forename: Hui
authors.initials: H
authors.lastname: Ling
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Ang
authors.forename: Shridhivya A
authors.initials: SA
authors.lastname: Reddy
authors.forename: Stephanie S-H
authors.initials: SS
authors.lastname: Lee
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Sock-Hoon
authors.initials: SH
authors.lastname: Tan
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
authors.forename: Wai-Keung
authors.initials: WK
authors.lastname: Chui
authors.forename: Eng-Hui
authors.initials: EH
authors.lastname: Chew
mesh_terms: D000818:Animals; D002396:Catechols / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D000072019:Kelch-Like ECH-Associated Protein 1; D061986:MCF-7 Cells; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002396:Catechols; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D010936:Plant Extracts; C040115:shogaol
keywords: ARE; COX-2; Chemoprevention; ECM; Ginger; HO-1; IKK; IκB kinase; IκBα; Keap1; Kelch-like ECH-associated protein 1; MMP; Michael acceptors; NAD(P)H quinone oxidoreductase-1; NF-E2 p45-related factor 2; NF-κB; NQO1; Nrf2; Nrf2-Keap1; PGE(2); PMA; Shogaols; antioxidant response element; cyclooxygenase-2; extracellular matrix; heme oxygenase-1; iNOS; inducible nitric oxide synthase; inhibitor of kappaBα; matrix metalloproteinase; nuclear factor-κB; phorbol 12-myristate 13-acetate; prostanglandin-E(2)