title: 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 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.
authors.affiliation: Laboratory of Pharmacotherapy, Yokohama College of Pharmacy, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Nitto
authors.forename: Kohei
authors.initials: K
authors.lastname: Sawaki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D044127:Epigenesis, Genetic / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000627:therapeutic use*; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide