{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,5]],"date-time":"2026-04-05T10:19:50Z","timestamp":1775384390351,"version":"3.50.1"},"reference-count":52,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2008,7,11]],"date-time":"2008-07-11T00:00:00Z","timestamp":1215734400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2008,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Folates can induce the expression and activity of the breast\u2010cancer\u2010resistance\u2010protein (BCRP) and the multidrug\u2010resistance\u2010protein\u20101 (MRP1). Our aim was to study the time\u2010dependent effect of folate deprivation\/supplementation on (<jats:italic>i<\/jats:italic>) BCRP and MRP expression and (<jats:italic>ii<\/jats:italic>) on drug resistance mediated by these transporters. Therefore Caco\u20102 colon cancer cells usually grown in standard RPMI\u2010medium containing supraphysiological folic acid (FA) concentrations (2.3 \u03bcM; high\u2010folate, HF) were gradually adapted to more physiological folate concentrations (1 nM leucovorin (LV) or 1 nM FA; low\u2010folate, LF), resulting in the sublines Caco\u20102\u2010LF\/LV and Caco\u20102\u2010LF\/FA. Caco\u20102\u2010LF\/LV and LF\/FA cells exhibited a maximal increase of 5.2\u2010 and 9.6\u2010fold for BCRP\u2010mRNA and 3.9\u2010 and 5.7\u2010fold for BCRP protein expression, respectively, but no major changes on MRP expression. Overexpression of BCRP in the LF\u2010cells resulted in 3.6\u2010 to 6.3\u2010fold resistance to mitoxantrone (MR), which was completely reverted by the BCRP inhibitor Ko143. On the other hand, LF\u2010adapted cells were markedly more sensitive to methotrexate than the HF\u2010counterpart, both after 4\u2010hr (9,870\u2010 and 23,923\u2010fold for Caco\u20102\u2010LF\/LV and LF\/FA, respectively) and 72\u2010hr (11\u2010 and 22\u2010fold for Caco\u20102\u2010LF\/LV and LF\/FA, respectively) exposure. Immunofluorescent staining observed with a confocal\u2010laser\u2010scan\u2010microscope revealed that in Caco\u20102 cells (both HF and LF), BCRP is mainly located in the cytoplasm. In conclusion, folate deprivation induces BCRP expression associated with MR resistance in Caco\u20102 cells. The intracellular localization of BCRP in these cells suggests that this transporter is not primarily extruding its substrates out of the cell, but rather to an intracellular compartment where folates can be kept as storage. \u00a9 2008 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ijc.23677","type":"journal-article","created":{"date-parts":[[2008,7,11]],"date-time":"2008-07-11T15:22:37Z","timestamp":1215789757000},"page":"1712-1720","source":"Crossref","is-referenced-by-count":26,"title":["Folate deprivation induces BCRP (ABCG2) expression and mitoxantrone resistance in Caco\u20102 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