Inhibition of bladder cancer by broccoli isothiocyanates sulforaphane and erucin: characterization, metabolism, and interconversion.

Abstract

SCOPE:

Epidemiologic evidence suggests diets rich in cruciferous vegetables, particularly broccoli, are associated with lower bladder cancer risk. Our objectives are to investigate these observations and determine the role of isothiocyanates in primary or secondary bladder cancer prevention.

METHODS AND RESULTS:

We initially investigate the mechanisms whereby broccoli and broccoli sprout extracts and pure isothiocyanates inhibit normal, noninvasive (RT4), and invasive (J82, UMUC3) human urothelial cell viability. Sulforaphane (IC(50) = 5.66 ± 1.2 μM) and erucin (IC(50) = 8.79 ± 1.3 μM) are found to be the most potent inhibitors and normal cells are least sensitive. This observation is associated with downregulation of survivin, epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/neu), G(2) /M cell cycle accumulation, and apoptosis. In a murine UMUC3 xenograft model, we fed semipurified diets containing 4% broccoli sprouts, or 2% broccoli sprout isothiocyanate extract; or gavaged pure sulforaphane or erucin (each at 295 μmol/kg, similar to dietary exposure); and report tumor weight reduction of 42% (p = 0.02), 42% (p = 0.04), 33% (p = 0.04), and 58% (p < 0.0001), respectively. Sulforaphane and erucin metabolites are present in mouse plasma (micromolar range) and tumor tissue, with N-acetylcysteine conjugates as the most abundant. Interconversion of sulforaphane and erucin metabolites was observed.

CONCLUSION:

This work supports development of fully characterized, novel food products containing broccoli components for phase I/II human studies targeting bladder cancer prevention.

• Authors: Besma Abbaoui, Kenneth M Riedl, Robin A Ralston, Jennifer M Thomas-Ahner, Steven J Schwartz, Steven K Clinton, Amir Mortazavi
• Journal: Molecular nutrition & food research (Mol Nutr Food Res) Vol. 56 Issue 11 Pg. 1675-87 (Nov 2012) ISSN: 1613-4133 [Electronic] Germany
• PMID: 23038615 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Anticarcinogenic Agents
• Antineoplastic Agents, Phytogenic
• BIRC5 protein, human
• Glucosinolates
• Inhibitor of Apoptosis Proteins
• Isothiocyanates
• Plant Extracts
• Sulfides
• Sulfoxides
• Survivin
• Thiocyanates
• erucin
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• sulforaphane

Topics

• Animals
• Anticarcinogenic Agents (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Brassica (chemistry, growth & development, metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• ErbB Receptors (metabolism)
• Female
• Glucosinolates (analysis, metabolism)
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Isothiocyanates
• Mice
• Mice, Nude
• Plant Extracts (chemistry, pharmacology)
• Receptor, ErbB-2 (metabolism)
• Sulfides (metabolism, pharmacokinetics, pharmacology)
• Sulfoxides
• Survivin
• Thiocyanates (metabolism, pharmacokinetics, pharmacology)
• Urinary Bladder Neoplasms (metabolism, pathology, prevention & control)
• Xenograft Model Antitumor Assays