TY - JOUR
T1 - Sulforaphane preconditioning sensitizes human colon cancer cells towards the bioreductive anticancer prodrug PR-104A
AU - Erzinger, Melanie M.
AU - Bovet, Cédric
AU - Hecht, Katrin M.
AU - Senger, Sabine
AU - Winiker, Pascale
AU - Sobotzki, Nadine
AU - Cristea, Simona
AU - Beerenwinkel, Niko
AU - Shay, Jerry W.
AU - Marra, Giancarlo
AU - Wollscheid, Bernd
AU - Sturla, Shana J.
N1 - Funding Information:
This work was supported by the Swiss National Science Foundation (136247), www.snf.ch. We gratefully acknowledge Dr. Maria Pavlou (ETH Zurich) for assistance with SILAC data analysis. We thank Prof. Dalibor Sames (Columbia University, NY, USA) for providing coumberone, Proacta for PR104A, and Dr. Adrian Blaser and Prof. Bill Wilson (Auckland Cancer Society Research Centre, University of Auckland, New Zealand) for SN34037. We are grateful to the Functional Genomics Center Zurich for technical support, especially to Dr. Jonas Grossmann, Dr. Peter Gehrig and Claudia Fortes.
Publisher Copyright:
© 2016 Erzinger et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2016/3
Y1 - 2016/3
N2 - 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 uM 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.
AB - 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 uM 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.
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U2 - 10.1371/journal.pone.0150219
DO - 10.1371/journal.pone.0150219
M3 - Article
C2 - 26950072
AN - SCOPUS:84961784305
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 3
M1 - e150219
ER -