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Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs

The concept of differentiation therapy of cancer is ~40 years old. Despite many encouraging results obtained in laboratories, both in vitro and in vivo studies, the only really successful clinical application of differentiation therapy was all-trans-retinoic acid (ATRA)-based therapy of acute promye...

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Autores principales: Marchwicka, Aleksandra, Cebrat, Małgorzata, Sampath, Preetha, Śnieżewski, Łukasz, Marcinkowska, Ewa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034350/
https://www.ncbi.nlm.nih.gov/pubmed/24904835
http://dx.doi.org/10.3389/fonc.2014.00125
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author Marchwicka, Aleksandra
Cebrat, Małgorzata
Sampath, Preetha
Śnieżewski, Łukasz
Marcinkowska, Ewa
author_facet Marchwicka, Aleksandra
Cebrat, Małgorzata
Sampath, Preetha
Śnieżewski, Łukasz
Marcinkowska, Ewa
author_sort Marchwicka, Aleksandra
collection PubMed
description The concept of differentiation therapy of cancer is ~40 years old. Despite many encouraging results obtained in laboratories, both in vitro and in vivo studies, the only really successful clinical application of differentiation therapy was all-trans-retinoic acid (ATRA)-based therapy of acute promyelocytic leukemia (APL). ATRA, which induces granulocytic differentiation of APL leukemic blasts, has revolutionized the therapy of this disease by converting it from a fatal to a curable one. However, ATRA does not work for other acute myeloid leukemias (AMLs). Since 1,25-dihydroxyvitamin D(3) (1,25D) is capable of inducing monocytic differentiation of leukemic cells, the idea of treating other AMLs with vitamin D analogs (VDAs) was widely accepted. Also, some types of solid cancers responded to in vitro applied VDAs, and hence it was postulated that VDAs can be used in many clinical applications. However, early clinical trials in which cancer patients were treated either with 1,25D or with VDAs, did not lead to conclusive results. In order to search for a molecular basis of such unpredictable responses of AML patients toward VDAs, we performed ex vivo experiments using patient’s blast cells. Experiments were also performed using 1,25D-responsive and 1,25D-non-responsive cell lines, to study their mechanisms of resistance toward 1,25D-induced differentiation. We found that one of the possible reasons might be due to a very low expression level of vitamin D receptor (VDR) mRNA in resistant cells, which can be increased by exposing the cells to ATRA. Our considerations concerning the molecular mechanism behind the low VDR expression and its regulation by ATRA are reported in this paper.
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spelling pubmed-40343502014-06-05 Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs Marchwicka, Aleksandra Cebrat, Małgorzata Sampath, Preetha Śnieżewski, Łukasz Marcinkowska, Ewa Front Oncol Oncology The concept of differentiation therapy of cancer is ~40 years old. Despite many encouraging results obtained in laboratories, both in vitro and in vivo studies, the only really successful clinical application of differentiation therapy was all-trans-retinoic acid (ATRA)-based therapy of acute promyelocytic leukemia (APL). ATRA, which induces granulocytic differentiation of APL leukemic blasts, has revolutionized the therapy of this disease by converting it from a fatal to a curable one. However, ATRA does not work for other acute myeloid leukemias (AMLs). Since 1,25-dihydroxyvitamin D(3) (1,25D) is capable of inducing monocytic differentiation of leukemic cells, the idea of treating other AMLs with vitamin D analogs (VDAs) was widely accepted. Also, some types of solid cancers responded to in vitro applied VDAs, and hence it was postulated that VDAs can be used in many clinical applications. However, early clinical trials in which cancer patients were treated either with 1,25D or with VDAs, did not lead to conclusive results. In order to search for a molecular basis of such unpredictable responses of AML patients toward VDAs, we performed ex vivo experiments using patient’s blast cells. Experiments were also performed using 1,25D-responsive and 1,25D-non-responsive cell lines, to study their mechanisms of resistance toward 1,25D-induced differentiation. We found that one of the possible reasons might be due to a very low expression level of vitamin D receptor (VDR) mRNA in resistant cells, which can be increased by exposing the cells to ATRA. Our considerations concerning the molecular mechanism behind the low VDR expression and its regulation by ATRA are reported in this paper. Frontiers Media S.A. 2014-05-27 /pmc/articles/PMC4034350/ /pubmed/24904835 http://dx.doi.org/10.3389/fonc.2014.00125 Text en Copyright © 2014 Marchwicka, Cebrat, Sampath, Śnieżewski and Marcinkowska. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Marchwicka, Aleksandra
Cebrat, Małgorzata
Sampath, Preetha
Śnieżewski, Łukasz
Marcinkowska, Ewa
Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs
title Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs
title_full Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs
title_fullStr Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs
title_full_unstemmed Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs
title_short Perspectives of Differentiation Therapies of Acute Myeloid Leukemia: The Search for the Molecular Basis of Patients’ Variable Responses to 1,25-Dihydroxyvitamin D and Vitamin D Analogs
title_sort perspectives of differentiation therapies of acute myeloid leukemia: the search for the molecular basis of patients’ variable responses to 1,25-dihydroxyvitamin d and vitamin d analogs
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034350/
https://www.ncbi.nlm.nih.gov/pubmed/24904835
http://dx.doi.org/10.3389/fonc.2014.00125
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