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Here, we have investigated the role of transporters and drug-metabolizing enzymes in this poor outcome. The expression levels (RT-qPCR) of potentially responsible genes in blasts collected at diagnosis were related to the subsequent response to two-cycle induction chemotherapy. The high expression of uptake carriers (ENT2), export ATP-binding cassette (ABC) pumps (MDR1), and enzymes (DCK, 5-NT, and CDA) in the blasts was associated with a lower response. Moreover, the sensitivity to cytarabine in AML cell lines was associated with ENT2 expression, whereas the expression of ABC pumps and enzymes was reduced. No ability of any AML cell line to export idarubicin through the ABC pumps, MDR1 and MRP, was found. The exposure of AML cells to cytarabine or idarubicin upregulated the detoxifying enzymes (5-NT and DCK). In AML patients, 5-NT and DCK expression was associated with the lack of response to induction chemotherapy (high sensitivity and specificity). In conclusion, in the blasts of AML patients, the reduction of the intracellular concentration of the active metabolite of cytarabine, mainly due to the increased expression of inactivating enzymes, can determine the response to induction chemotherapy.<\/jats:p>","DOI":"10.3390\/cancers15123145","type":"journal-article","created":{"date-parts":[[2023,6,12]],"date-time":"2023-06-12T01:59:07Z","timestamp":1686535147000},"page":"3145","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Role of Intracellular Drug Disposition in the Response of Acute Myeloid Leukemia to Cytarabine and Idarubicin Induction Chemotherapy"],"prefix":"10.3390","volume":"15","author":[{"given":"Gabriela","family":"Rodr\u00edguez-Mac\u00edas","sequence":"first","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Department of Hematology, Gregorio Mara\u00f1\u00f3n General University Hospital, 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6891-1554","authenticated-orcid":false,"given":"Oscar","family":"Briz","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0430-838X","authenticated-orcid":false,"given":"Candela","family":"Cives-Losada","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-6059","authenticated-orcid":false,"given":"Mar\u00eda C.","family":"Chill\u00f3n","sequence":"additional","affiliation":[{"name":"Hematology, Biomedical Research Institute of Salamanca, Salamanca University Hospital, 37007 Salamanca, Spain"},{"name":"CIBER in Oncology (CIBER-ONC), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Mart\u00ednez-Laperche","sequence":"additional","affiliation":[{"name":"Department of Hematology, Gregorio Mara\u00f1\u00f3n General University Hospital, 28007 Madrid, Spain"},{"name":"Gregorio Mara\u00f1\u00f3n Health Research Institute (IiSGM), 28007 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibon","family":"Mart\u00ednez-Arranz","sequence":"additional","affiliation":[{"name":"OWL Metabolomics, Bizkaia Technology Park, 48160 Derio, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4931-9170","authenticated-orcid":false,"given":"Ismael","family":"Bu\u00f1o","sequence":"additional","affiliation":[{"name":"Department of Hematology, Gregorio Mara\u00f1\u00f3n General University Hospital, 28007 Madrid, Spain"},{"name":"Gregorio Mara\u00f1\u00f3n Health Research Institute (IiSGM), 28007 Madrid, Spain"},{"name":"Department of Cell Biology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Gonz\u00e1lez-D\u00edaz","sequence":"additional","affiliation":[{"name":"Hematology, Biomedical Research Institute of Salamanca, Salamanca University Hospital, 37007 Salamanca, Spain"},{"name":"CIBER in Oncology (CIBER-ONC), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 L.","family":"D\u00edez-Mart\u00edn","sequence":"additional","affiliation":[{"name":"Department of Hematology, Gregorio Mara\u00f1\u00f3n General University Hospital, 28007 Madrid, Spain"},{"name":"Gregorio Mara\u00f1\u00f3n Health Research Institute (IiSGM), 28007 Madrid, Spain"},{"name":"Department of Medicine, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1186-6849","authenticated-orcid":false,"given":"Jose J. 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R.","family":"Macias","sequence":"additional","affiliation":[{"name":"Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Biomedical Research Institute of Salamanca (IBSAL), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.blre.2015.08.001","article-title":"Role of drug transport and metabolism in the chemoresistance of acute myeloid leukemia","volume":"30","author":"Marin","year":"2016","journal-title":"Blood Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1182\/blood-2014-10-551911","article-title":"How I treat refractory and early relapsed acute myeloid leukemia","volume":"126","author":"Thol","year":"2015","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/aps.2013.131","article-title":"The role of reduced intracellular concentrations of active drugs in the lack of response to anticancer chemotherapy","volume":"35","author":"Marin","year":"2014","journal-title":"Acta Pharmacol. 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