Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic
Abstract.: Acute promyelocytic leukemia (APL) is characterized by the occurrence of translocations between chromosomes 15 and 17, resulting in generation of a fusion protein of promyelocytic leukemia (PML) and retinoid A receptor (RAR) α. APL cells are unable to differentiate into mature granulocyte...
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| Format: | Article |
| Language: | English |
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Elsevier
2014-04-01
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| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1347861319300726 |
| _version_ | 1818153406554963968 |
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| author | Takeaki Nitto Kohei Sawaki |
| author_facet | Takeaki Nitto Kohei Sawaki |
| author_sort | Takeaki Nitto |
| collection | DOAJ |
| description | Abstract.: Acute promyelocytic leukemia (APL) is characterized by the occurrence of translocations between chromosomes 15 and 17, resulting in generation of a fusion protein of promyelocytic leukemia (PML) and retinoid A receptor (RAR) α. APL cells are unable to differentiate into mature granulocytes since PML-RARα functions as a strong transcriptional repressor for a gene involved in granulocyte differentiation. All-trans retinoic acid (ATRA) is the first agent that has been developed to target specific disease-causing molecules, i.e., ATRA suppresses abnormal functions of oncogenic proteins. Moreover, ATRA facilitates the differentiation of APL cells toward mature granulocytes by changing epigenetic modifiers from corepressor complexes to co-activator complexes on target genes after binding to the ligand-binding domain at the RARα moiety of the PML-RARα oncoprotein. On the other hand, arsenic trioxide (ATO), another promising agent used to treat APL, directly binds to the PML moiety of the PML-RARα protein, causing oxidation and multimerization. ATO enhances the conjugation of small ubiquitin-like modifiers to PML-RARα, followed by ubiquitination and degradation, relieving the genes associated with granulocytic differentiation from suppressive restraint by the oncoprotein. Recent clinical studies have demonstrated that combination therapy with both ATRA and ATO is useful to achieve remission. Keywords:: acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, retinoic acid receptor, epigenetics |
| first_indexed | 2024-12-11T14:10:07Z |
| format | Article |
| id | doaj.art-e2d445b2311348d4a426badcfd65f026 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-11T14:10:07Z |
| publishDate | 2014-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-e2d445b2311348d4a426badcfd65f0262022-12-22T01:03:29ZengElsevierJournal of Pharmacological Sciences1347-86132014-04-011263179185Molecular Mechanisms of the Antileukemia Activities of Retinoid and ArsenicTakeaki Nitto0Kohei Sawaki1Laboratory of Pharmacotherapy, Yokohama College of Pharmacy, Yokohama, Kanagawa 245-0066, Japan; Corresponding author. nitto@hamayaku.ac.jpLaboratory of Pharmacotherapy, Yokohama College of Pharmacy, Yokohama, Kanagawa 245-0066, JapanAbstract.: Acute promyelocytic leukemia (APL) is characterized by the occurrence of translocations between chromosomes 15 and 17, resulting in generation of a fusion protein of promyelocytic leukemia (PML) and retinoid A receptor (RAR) α. APL cells are unable to differentiate into mature granulocytes since PML-RARα functions as a strong transcriptional repressor for a gene involved in granulocyte differentiation. All-trans retinoic acid (ATRA) is the first agent that has been developed to target specific disease-causing molecules, i.e., ATRA suppresses abnormal functions of oncogenic proteins. Moreover, ATRA facilitates the differentiation of APL cells toward mature granulocytes by changing epigenetic modifiers from corepressor complexes to co-activator complexes on target genes after binding to the ligand-binding domain at the RARα moiety of the PML-RARα oncoprotein. On the other hand, arsenic trioxide (ATO), another promising agent used to treat APL, directly binds to the PML moiety of the PML-RARα protein, causing oxidation and multimerization. ATO enhances the conjugation of small ubiquitin-like modifiers to PML-RARα, followed by ubiquitination and degradation, relieving the genes associated with granulocytic differentiation from suppressive restraint by the oncoprotein. Recent clinical studies have demonstrated that combination therapy with both ATRA and ATO is useful to achieve remission. Keywords:: acute promyelocytic leukemia, all-trans retinoic acid, arsenic trioxide, retinoic acid receptor, epigeneticshttp://www.sciencedirect.com/science/article/pii/S1347861319300726 |
| spellingShingle | Takeaki Nitto Kohei Sawaki Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic Journal of Pharmacological Sciences |
| title | Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic |
| title_full | Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic |
| title_fullStr | Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic |
| title_full_unstemmed | Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic |
| title_short | Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic |
| title_sort | molecular mechanisms of the antileukemia activities of retinoid and arsenic |
| url | http://www.sciencedirect.com/science/article/pii/S1347861319300726 |
| work_keys_str_mv | AT takeakinitto molecularmechanismsoftheantileukemiaactivitiesofretinoidandarsenic AT koheisawaki molecularmechanismsoftheantileukemiaactivitiesofretinoidandarsenic |