The chemoprotective properties of
sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of
xenobiotic-metabolizing and
antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of
cancer therapy through the modulation of
drug-metabolizing
enzymes. To identify
proteins modulated by a low concentration of SF, we treated HT29
colon cancer cells with 2.5 μM SF.
Protein abundance changes were detected by stable
isotope labeling of
amino acids in cell culture. Among 18
proteins found to be significantly up-regulated,
aldo-keto reductase 1C3 (AKR1C3), bioactivating the
DNA cross-linking
prodrug PR-104A, was further characterized. Preconditioning HT29 cells with SF reduced the EC50 of
PR-104A 3.6-fold. The increase in
PR-104A cytotoxicity was linked to AKR1C3 abundance and activity, both induced by SF in a dose-dependent manner. This effect was reproducible in a second
colon cancer cell line, SW620, but not in other
colon cancer cell lines where AKR1C3 abundance and activity were absent or barely detectable and could not be induced by SF. Interestingly, SF had no significant influence on
PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of
PR-104A after preconditioning with SF was apparent only in
cancer cells provided that AKR1C3 is expressed, while its expression in non-cancerous cells did not elicit such a response. Therefore, a subset of
cancers may be susceptible to combined food-derived component and
prodrug treatments with no harm to normal tissues.