Molecular Mechanisms of the Antileukemia Activities of Retinoid and Arsenic
| Autor: | Kohei Sawaki, Takeaki Nitto |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Acute promyelocytic leukemia
Oncogene Proteins Fusion medicine.drug_class Retinoic acid Antineoplastic Agents Tretinoin Arsenicals Epigenesis Genetic chemistry.chemical_compound Promyelocytic leukemia protein Arsenic Trioxide Leukemia Promyelocytic Acute Antineoplastic Combined Chemotherapy Protocols medicine Biomarkers Tumor Animals Humans Retinoid Arsenic trioxide neoplasms Pharmacology biology Gene Expression Regulation Leukemic lcsh:RM1-950 Drug Synergism Oxides medicine.disease Fusion protein Retinoic acid receptor Treatment Outcome lcsh:Therapeutics. Pharmacology chemistry biology.protein Cancer research Molecular Medicine Corepressor |
| Zdroj: | Journal of Pharmacological Sciences, Vol 126, Iss 3, Pp 179-185 (2014) |
| ISSN: | 1347-8613 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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