A novel shogaol analog suppresses cancer cell invasion and inflammation, and displays cytoprotective effects through modulation of NF-κB and Nrf2-Keap1 signaling pathways

Toxicol Appl Pharmacol. 2013 Nov 1;272(3):852-62. doi: 10.1016/j.taap.2013.07.011. Epub 2013 Jul 27.


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.

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Catechols / chemistry
  • Catechols / pharmacology*
  • Catechols / therapeutic use
  • Cytoprotection / drug effects*
  • Cytoprotection / physiology
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • HEK293 Cells
  • Humans
  • Inflammation / metabolism
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Kelch-Like ECH-Associated Protein 1
  • MCF-7 Cells
  • Mice
  • NF-E2-Related Factor 2 / physiology*
  • NF-kappa B / physiology*
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / prevention & control*
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Plant Extracts / therapeutic use
  • Signal Transduction / drug effects
  • Signal Transduction / physiology


  • Catechols
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NF-kappa B
  • NFE2L2 protein, human
  • Plant Extracts
  • shogaol