CYP24A1 inhibition facilitates the anti-tumor effect of vitamin D3 on colorectal cancer cells

János P. Kósa, Péter Horváth, János Wölfing, Dóra Kovács, Bernadett Balla, Péter Mátyus, Evelin Horváth, Gábor Speer, István Takács, Zsolt Nagy, Henrik Horváth, Péter Lakatos

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22 Citations (Scopus)

Abstract

AIM: The effects of vitamin D3 have been investigated on various tumors, including colorectal cancer (CRC). 25-hydroxyvitamin-D3-24-hydroxylase (CYP24A1), the enzyme that inactivates the active vitamin D3 metabolite 1,25-dihydroxyvitamin D3 (1,25-D3), is considered to be the main enzyme determining the biological half-life of 1,25-D3. During colorectal carcinogenesis, the expression and concentration of CYP24A1 increases significantly, suggesting that this phenomenon could be responsible for the proposed efficacy of 1,25-D3 in the treatment of CRC. The aim of this study was to investigate the anti-tumor effects of vitamin D3 on the human CRC cell line Caco-2 after inhibition of the cytochrome P450 component of CYP24A1 activity. METHODS: We examined the expression of CYP24A1 mRNA and the effects of 1,25-D3 on the cell line Caco-2 after inhibition of CYP24A1. Cell viability and proliferation were determined by means of sulforhoda-mine-B staining and bromodeoxyuridine incorporation, respectively, while cytotoxicity was estimated via the lactate dehydrogenase content of the cell culture supernatant. CYP24A1 expression was measured by realtime reverse transcription polymerase chain reaction. A number of tetralone compounds were synthesized to investigate their CP24A1 inhibitory activity. RESULTS: In response to 1,25-D3, CYP24A1 mRNA expression was enhanced significantly, in a time- and dose-dependent manner. Caco-2 cell viability and proliferation were not influenced by the administration of 1,25-D3 alone, but were markedly reduced by co-administration of 1,25-D3 and KD-35, a CYP24A1-inhib-iting tetralone. Our data suggest that the mechanism of action of co-administered KD-35 and 1,25-D3 does not involve a direct cytotoxic effect, but rather the inhibition of cell proliferation. CONCLUSION: These findings demonstrate that the selective inhibition of CYP24A1 by compounds such as KD-35 may be a new approach for enhancement of the anti-tumor effect of 1,25-D3 on CRC.

Original languageEnglish
Pages (from-to)2621-2628
Number of pages8
JournalWorld journal of gastroenterology
Volume19
Issue number17
DOIs
Publication statusPublished - May 7 2013

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Keywords

  • CYP24A1 inhibition
  • Caco-2 cell culture
  • Colorectal cancer
  • Tetralone derivatives
  • Vitamin D3

ASJC Scopus subject areas

  • Gastroenterology

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