title: Sulforaphane Preconditioning Sensitizes Human Colon Cancer Cells towards the Bioreductive Anticancer Prodrug PR-104A.
abstract: 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.
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Erzinger
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Cédric
authors.initials: C
authors.lastname: Bovet
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Katrin M
authors.initials: KM
authors.lastname: Hecht
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Senger
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Pascale
authors.initials: P
authors.lastname: Winiker
authors.affiliation: Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Nadine
authors.initials: N
authors.lastname: Sobotzki
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.|SIB Swiss Institute of Bioinformatics, Basel, Switzerland.
authors.forename: Simona
authors.initials: S
authors.lastname: Cristea
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.|SIB Swiss Institute of Bioinformatics, Basel, Switzerland.
authors.forename: Niko
authors.initials: N
authors.lastname: Beerenwinkel
authors.affiliation: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.|Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, Zurich, Switzerland.|BioMedical Proteomics Platform (BMPP), ETH Zurich, Zurich, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollscheid
authors.affiliation: Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.
authors.forename: Shana J
authors.initials: SJ
authors.lastname: Sturla
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000074425:Aldo-Keto Reductase Family 1 Member C3; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001692:Biological Transport; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D004171:Diploidy; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D017879:Isothiocyanates / Q000378:metabolism / Q000494:pharmacology*; D009588:Nitrogen Mustard Compounds / Q000009:adverse effects / Q000494:pharmacology*; D011355:Prodrugs / Q000009:adverse effects / Q000494:pharmacology; D013454:Sulfoxides
chemical_list: D000970:Antineoplastic Agents; D017879:Isothiocyanates; D009588:Nitrogen Mustard Compounds; C524170:PR-104A; D011355:Prodrugs; D013454:Sulfoxides; D015096:3-Hydroxysteroid Dehydrogenases; D006911:Hydroxyprostaglandin Dehydrogenases; C487341:AKR1C3 protein, human; D000074425:Aldo-Keto Reductase Family 1 Member C3; C016766:sulforaphane