The Cinnamon-Derived Michael Acceptor Cinnamic Aldehyde Impairs Melanoma Cell Proliferation, Invasiveness, and Tumor Growth

Free Radic Biol Med. 2009 Jan 15;46(2):220-31. doi: 10.1016/j.freeradbiomed.2008.10.025. Epub 2008 Nov 1.

Abstract

Redox dysregulation in cancer cells represents a chemical vulnerability that can be targeted by pro-oxidant redox intervention. Dietary constituents that contain an electrophilic Michael acceptor pharmacophore may therefore display promising chemopreventive and chemotherapeutic anti-cancer activity. Here, we demonstrate that the cinnamon-derived dietary Michael acceptor trans-cinnamic aldehyde (CA) impairs melanoma cell proliferation and tumor growth. Feasibility of therapeutic intervention using high doses of CA (120 mg/kg, po, daily, 10 days) was demonstrated in a human A375 melanoma SCID mouse xenograft model. Low-micromolar concentrations (IC(50)< 10 microM) of CA, but not closely related CA derivatives devoid of Michael acceptor activity, suppressed proliferation of human metastatic melanoma cell lines (A375, G361, LOX) with G1 cell-cycle arrest, elevated intracellular ROS, and impaired invasiveness. Expression array analysis revealed that CA induced an oxidative stress response in A375 cells, up-regulating heme oxygenase 1, sulfiredoxin 1 homolog, thioredoxin reductase 1, and other genes, including the cell-cycle regulator and stress-responsive tumor suppressor gene cyclin-dependent kinase inhibitor 1A, a key mediator of G1-phase arrest. CA, but not Michael-inactive derivatives, inhibited NF-kappaB transcriptional activity and TNFalpha-induced IL-8 production in A375 cells. These findings support a previously unrecognized role of CA as a dietary Michael acceptor with potential anti-cancer activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrolein / analogs & derivatives*
  • Acrolein / pharmacology
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cinnamomum zeylanicum
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • G1 Phase / drug effects
  • Gene Expression Profiling
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Humans
  • Interleukin-8 / metabolism
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / pathology
  • Mice
  • Mice, SCID
  • Microarray Analysis
  • NF-kappa B / antagonists & inhibitors
  • Neoplasm Invasiveness / prevention & control
  • Neoplasm Transplantation
  • Oxidative Stress / drug effects
  • Oxidoreductases Acting on Sulfur Group Donors / genetics
  • Oxidoreductases Acting on Sulfur Group Donors / metabolism
  • Plant Growth Regulators / pharmacology*
  • Signal Transduction / drug effects
  • Thioredoxin Reductase 1 / genetics
  • Thioredoxin Reductase 1 / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p21
  • Interleukin-8
  • NF-kappa B
  • Plant Growth Regulators
  • Tumor Necrosis Factor-alpha
  • Acrolein
  • Heme Oxygenase-1
  • Oxidoreductases Acting on Sulfur Group Donors
  • Thioredoxin Reductase 1
  • SRXN1 protein, human
  • cinnamic aldehyde