title: Methylated arsenic metabolites bind to PML protein but do not induce cellular differentiation and PML-RARα protein degradation.
abstract: Arsenic trioxide (As2O3) is one of the most effective therapeutic agents used for patients with acute promyelocytic leukemia (APL). The probable explanation for As2O3-induced cell differentiation is the direct targeting of PML-RARα oncoprotein by As2O3, which results in initiation of PML-RARα degradation. However, after injection, As2O3 is rapidly methylated in body to different intermediate metabolites such as trivalent monomethylarsonous acid (MMA(III)) and dimethylarsinous acid (DMA(III)), therefore, it remains unknown that which arsenic specie is actually responsible for the therapeutic effects against APL. Here we have shown the role of As2O3 (as iAs(III)) and its intermediate metabolites (i.e., MMA(III)/DMA(III)) in NB4 cells. Inorganic iAs(III) predominantly showed induction of cell differentiation, while MMA(III) and DMA(III) specifically showed to induce mitochondria and endoplasmic reticulum-mediated apoptosis, respectively. On the other hand, in contrast to iAs(III), MMA(III) showed stronger binding affinity for ring domain of PML recombinant protein, however, could not induce PML protein SUMOylation and ubiquitin/proteasome degradation. In summary, our results suggest that the binding of arsenicals to the ring domain of PML proteins is not associated with the degradation of PML-RARα fusion protein. Moreover, methylated arsenicals can efficiently lead to cellular apoptosis, however, they are incapable of inducing NB4 cell differentiation.
authors.affiliation: Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China.|College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qian Qian
authors.initials: QQ
authors.lastname: Wang
authors.affiliation: Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China.|College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xin Yi
authors.initials: XY
authors.lastname: Zhou
authors.affiliation: Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China.|College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Yan Fang
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Na
authors.initials: N
authors.lastname: Bu
authors.affiliation: Department of Hematology and Oncology, The First Clinical College of Harbin Medical University, Harbin 150086, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Hematology and Oncology, The First Clinical College of Harbin Medical University, Harbin 150086, China.
authors.forename: Feng Lin
authors.initials: FL
authors.lastname: Cao
authors.affiliation: Department of Toxicology, School of Medicine and Public Health, Zhejiang University, Hangzhou 310058, China.|College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Naranmandura
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism* / Q000494:pharmacology*; D001711:Biotransformation; D002101:Cacodylic Acid / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D009687:Nuclear Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology; D010087:Oxides / Q000378:metabolism* / Q000494:pharmacology*; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis; D058207:Sumoylation; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D009942:Organometallic Compounds; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C472511:dimethylarsinous acid; C406082:monomethylarsonous acid; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D002101:Cacodylic Acid; D046988:Proteasome Endopeptidase Complex; D000077237:Arsenic Trioxide
keywords: acute promyelocytic leukemia; arsenic binding proteins; arsenic trioxide; monomethylarsonous acid; trivalent arsenicals