title: Metabolism of arsenic trioxide in acute promyelocytic leukemia cells.
abstract: Arsenic trioxide (As2O3) effectively induces complete clinical and molecular remissions in acute promyelocytic leukemia (APL) patients and triggers apoptosis in APL cells. The effect induced by As2O3 is also associated with extensive genomic-wide epigenetic changes with large-scale alterations in DNA methylation. We investigated the As2O3 metabolism in association with factors involved in the production of its methylated metabolites in APL-derived cell line, NB4. We used high performance liquid chromatography (HPLC) technique to detect As2O3 metabolites in NB4 cells. The effects of As2O3 on glutathione level, S-Adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) levels were investigated. Also, we studied the expression levels of arsenic methyltransferase (AS3MT) and DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) by real-time PCR. Our results show that after As2O3 entry into the cell, it was converted into methylated metabolites, mono-methylarsenic (MMA) and dimethylarsenic (DMA). The glutathione (GSH) production was increased in parallel with the methylated metabolites formations. As2O3 treatment inhibited DNMTs (DNMT1, DNMT3a, and DNMT3b) in dose- and time-dependent manners. The SAH levels in As2O3-treated cells were increased; however, the SAM level was not affected. The present study shows that APL cell is capable of metabolizing As2O3. The continuous formation of intracellular methylated metabolites, the inhibition of DNMTs expression levels and the increase of SAH level by As2O3 biotransformation would probably affect the DNMTs-methylated DNA methylation in a manner related to the extent of DNA hypomethylation. Production of intracellular methylated metabolites and epigenetic changes of DNA methylation during As2O3 metabolism may contribute to the therapeutic effect of As2O3 in APL.
authors.affiliation: Institute of Biochemistry and Biophysics (IBB), University of Tehran, P.O. Box 13145-1384, Tehran, Iran; Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Khaleghian
authors.forename: Seyed H
authors.initials: SH
authors.lastname: Ghaffari
authors.forename: Shahin
authors.initials: S
authors.lastname: Ahmadian
authors.forename: Kamran
authors.initials: K
authors.lastname: Alimoghaddam
authors.forename: Ardeshir
authors.initials: A
authors.lastname: Ghavamzadeh
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism* / Q000627:therapeutic use; D002101:Cacodylic Acid / Q000378:metabolism; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000096:biosynthesis / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects*; D000090205:DNA Methyltransferase 3A; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000378:metabolism*; D008780:Methyltransferases / Q000096:biosynthesis / Q000378:metabolism; D010087:Oxides / Q000378:metabolism* / Q000627:therapeutic use; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D002101:Cacodylic Acid; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D005978:Glutathione; D008780:Methyltransferases; D010087:Oxides; D012435:S-Adenosylhomocysteine; D012436:S-Adenosylmethionine; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C505756:AS3MT protein, human; C000619380:DNMT1 protein, human
keywords: ACUTE PROMYELOCYTIC LEUKEMIA; ARSENIC METHYLTRANSFERASE; ARSENIC TRIOXIDE; DIMETHYLARSENIC (DMA); DNA METHYLTRANSFERASES; MONO-METHYLARSENIC (MMA); NB4