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 sulforhodamine-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 real-time 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-inhibiting 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.
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 sulforhodamine-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 real-time 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-inhibiting 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.
Authors: Dae S Rheem; David J Baylink; Snorri Olafsson; Christian S Jackson; Michael H Walter Journal: Scand J Gastroenterol Date: 2010-08 Impact factor: 2.423
Authors: Ahmed S Aboraia; Bart Makowski; Alba Bahja; David Prosser; Andrea Brancale; Glenville Jones; Claire Simons Journal: Eur J Med Chem Date: 2010-07-08 Impact factor: 6.514
Authors: Richard Edlich; Shelley S Mason; Margot E Chase; Allyson L Fisher; K Gubler; William B Long; Jerry D Giesy; Marni L Foley Journal: J Environ Pathol Toxicol Oncol Date: 2009 Impact factor: 3.567
Authors: Mazda Jenab; H Bas Bueno-de-Mesquita; Pietro Ferrari; Franzel J B van Duijnhoven; Teresa Norat; Tobias Pischon; Eugène H J M Jansen; Nadia Slimani; Graham Byrnes; Sabina Rinaldi; Anne Tjønneland; Anja Olsen; Kim Overvad; Marie-Christine Boutron-Ruault; Françoise Clavel-Chapelon; Sophie Morois; Rudolf Kaaks; Jakob Linseisen; Heiner Boeing; Manuela M Bergmann; Antonia Trichopoulou; Gesthimani Misirli; Dimitrios Trichopoulos; Franco Berrino; Paolo Vineis; Salvatore Panico; Domenico Palli; Rosario Tumino; Martine M Ros; Carla H van Gils; Petra H Peeters; Magritt Brustad; Eiliv Lund; María-José Tormo; Eva Ardanaz; Laudina Rodríguez; Maria-José Sánchez; Miren Dorronsoro; Carlos A Gonzalez; Göran Hallmans; Richard Palmqvist; Andrew Roddam; Timothy J Key; Kay-Tee Khaw; Philippe Autier; Pierre Hainaut; Elio Riboli Journal: BMJ Date: 2010-01-21
Authors: Yamilka Abreu-Delgado; Raymond A Isidro; Esther A Torres; Alexandra González; Myrella L Cruz; Angel A Isidro; Carmen I González-Keelan; Priscilla Medero; Caroline B Appleyard Journal: World J Gastroenterol Date: 2016-04-07 Impact factor: 5.742
Authors: B Balla; B Tobiás; J P Kósa; J Podani; P Horváth; Z Nagy; J Horányi; B Járay; E Székely; L Krenács; K Árvai; M Dank; Z Putz; B Szabó; B Szili; Z Valkusz; B Vasas; G Győri; P Lakatos; I Takács Journal: J Endocrinol Invest Date: 2014-09-09 Impact factor: 4.256