Arsenic trioxide circumvents multidrug resistance based on different mechanisms in human leukemia cell lines.
To determine the antitumor effect of arsenic trioxide (As2O3) on multidrug-resistant cells, we applied 3 human leukemia cell lines: daunorubicin (DNR)-resistant cell line K562/D1-9, which overexpresses p-glycoprotein (Pgp); DNR and 1-beta-D-arabinofuranosylcytosine (Ara-C) double-resistant cell line HL60/AD, which overexpresses multidrug resistance-associated protein (MRP1); and Bcl-2-transfected pre-B lineage leukemia cell line 697/Bcl-2. Interestingly, K562/D1-9 showed collateral sensitivity. Only HL60/AD showed small cross resistance, but 697/Bcl-2 had no resistance to As2O3. An intracellular content of glutathione (GSH) played a critical role in sensitivity to As2O3. Buthionine-sulfoximine (BSO), which reduces the GSH content, not only increased the As2O3 sensitivity but also conquered the MRP1-related cross resistance in HL60/AD. In conclusion, As2O3 was effective in all 3 cell lines, suggesting that As2O3 may be a promising agent for the treatment of multidrug-resistant leukemia.
Seo
Tamami
T
First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, 910-1193, Japan.
Urasaki
Yoshimasa
Y
Takemura
Haruyuki
H
Ueda
Takanori
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D019008:Drug Resistance, Neoplasm; D019254:Genes, bcl-2 / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D019328:Buthionine Sulfoximine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010087:Oxides; D017382:Reactive Oxygen Species; C421109:multidrug resistance-associated protein 1