Sulforaphane preconditioning sensitizes human colon cancer cells towards the bioreductive anticancer prodrug PR-104A

Melanie M. Erzinger, Cédric Bovet, Katrin M. Hecht, Sabine Senger, Pascale Winiker, Nadine Sobotzki, Simona Cristea, Niko Beerenwinkel, Jerry W. Shay, Giancarlo Marra, Bernd Wollscheid, Shana J. Sturla

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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 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.

Original languageEnglish (US)
Article numbere150219
JournalPLoS One
Volume11
Issue number3
DOIs
StatePublished - Mar 1 2016

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Prodrugs
colorectal neoplasms
Colonic Neoplasms
Cells
cell lines
cytotoxicity
isotope labeling
neoplasms
proteins
xenobiotics
enzymes
crosslinking
Cytotoxicity
stable isotopes
Cell Line
cell culture
epithelial cells
vegetables
cells
antioxidants

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Erzinger, M. M., Bovet, C., Hecht, K. M., Senger, S., Winiker, P., Sobotzki, N., ... Sturla, S. J. (2016). Sulforaphane preconditioning sensitizes human colon cancer cells towards the bioreductive anticancer prodrug PR-104A. PLoS One, 11(3), [e150219]. https://doi.org/10.1371/journal.pone.0150219

Sulforaphane preconditioning sensitizes human colon cancer cells towards the bioreductive anticancer prodrug PR-104A. / Erzinger, Melanie M.; Bovet, Cédric; Hecht, Katrin M.; Senger, Sabine; Winiker, Pascale; Sobotzki, Nadine; Cristea, Simona; Beerenwinkel, Niko; Shay, Jerry W.; Marra, Giancarlo; Wollscheid, Bernd; Sturla, Shana J.

In: PLoS One, Vol. 11, No. 3, e150219, 01.03.2016.

Research output: Contribution to journalArticle

Erzinger, MM, Bovet, C, Hecht, KM, Senger, S, Winiker, P, Sobotzki, N, Cristea, S, Beerenwinkel, N, Shay, JW, Marra, G, Wollscheid, B & Sturla, SJ 2016, 'Sulforaphane preconditioning sensitizes human colon cancer cells towards the bioreductive anticancer prodrug PR-104A', PLoS One, vol. 11, no. 3, e150219. https://doi.org/10.1371/journal.pone.0150219
Erzinger, Melanie M. ; Bovet, Cédric ; Hecht, Katrin M. ; Senger, Sabine ; Winiker, Pascale ; Sobotzki, Nadine ; Cristea, Simona ; Beerenwinkel, Niko ; Shay, Jerry W. ; Marra, Giancarlo ; Wollscheid, Bernd ; Sturla, Shana J. / Sulforaphane preconditioning sensitizes human colon cancer cells towards the bioreductive anticancer prodrug PR-104A. In: PLoS One. 2016 ; Vol. 11, No. 3.
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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 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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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.

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