The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth

doi:10.1016/j.freeradbiomed.2008.10.025

Free Radical Biology and Medicine

Volume 46, Issue 2, 15 January 2009, Pages 220-231

https://doi.org/10.1016/j.freeradbiomed.2008.10.025 Get rights and content

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 (IC₅₀ < 10 μM) 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-κB transcriptional activity and TNFα-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.

Section snippets

Chemicals

All chemicals were from Sigma Chemical Co. (St. Louis, MO, USA).

Human melanoma SCID mouse xenograft model

A375 human melanoma cells were grown in HyQ RPMI 1640 medium (HyClone) supplemented with 10% fetal bovine serum (Omega Scientific) and maintained in 5% CO₂–95% air humidified atmosphere at 37 °C. Subconfluent cells were harvested by using 0.25% trypsin–EDTA (HyClone). Cells (> 90% viability) were resuspended at the concentration of 10 × 10⁶ cells /100 μl of sterile saline. A SCID mouse colony was developed at the University of Arizona

Oral administration of cinnamic aldehyde impairs growth of A375 human melanoma xenografts in SCID mice

Based on its known safety profile as a human dietary factor, its documented low acute toxicity in mice (oral LD₅₀ > 2 g/kg in mice [36]), and promising cell-based chemopreventive properties [32], we tested the thiol-reactive Michael acceptor CA as a potential inhibitor of tumor growth in a human melanoma SCID mouse xenograft model (Fig. 1). Daily oral CA treatment (120 mg/kg/day in 0.5% methylcellulose/PBS) of human A375 melanoma xenograft-bearing SCID mice induced a moderate suppression of

Discussion

The preferential sensitivity of melanoma cells to small-molecule pro-oxidant intervention [12], [13], [14], [15], [16], [18] and the documented anti-melanoma activity of electrophilic agents that share a Michael acceptor pharmacophore, including curcumin [40], [41], dimethylfumarate [15], omentosin, and inuviscolide [42], led us to evaluate the anti-melanoma activity of CA in vitro and in vivo. CA, a key flavor compound contained in the essential oil of cinnamon, contains an electrophilic

Acknowledgments

This work was supported in part by grants from the National Institutes of Health (R01CA122484, ES007091, Arizona Cancer Center Support Grant CA023074) and from the Arizona Biomedical Research Commission (ABRC 0721). Animal experimentation was performed at the AZCC Experimental Mouse Shared Service and tumor histology was performed at the Tissue Acquisition and Cellular/Molecular Analysis Shared Service.

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Original ContributionThe cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth

Abstract

Section snippets

Chemicals

Human melanoma SCID mouse xenograft model

Oral administration of cinnamic aldehyde impairs growth of A375 human melanoma xenografts in SCID mice

Discussion

Acknowledgments

Drug Resist. Update

Free Radic. Biol. Med.

Cancer Lett.

Semin. Cancer Biol.

Free Radic. Biol. Med.

J. Biol. Chem.

Food Chem. Toxicol.

Toxicol. Appl. Pharmacol.

Food Chem. Toxicol.

Int. J. Food Microbiol.

Eur. J. Pharmacol.

Free Radic. Biol. Med.

J. Biol. Chem.

Methods Enzymol.

Food Cosmet. Toxicol.

Free Radic. Biol. Med.

Toxicol. Appl. Pharmacol.

Biochem. Pharmacol.

Exp. Cell Res.

J. Biol. Chem.

Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma

Br. J. Dermatol.

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Mol. Cancer Ther.

An emerging molecular target in melanoma: cellular carbonyl stress and the inhibition of mitochondrial survival pathways by carbonyl scavenger agents

Curr. Cancer Ther. Rev.

New perspectives on melanoma pathogenesis and chemoprevention

Recent Results Cancer Res.

Reactive oxygen species from NAD(P)H:quinone oxidoreductase constitutively activate NF-kappaB in malignant melanoma cells

Am. J. Physiol. Cell Physiol.

Overexpression of Akt converts radial growth melanoma to vertical growth melanoma

J. Clin. Invest.

Original Contribution
The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth