Multidrug resistance protein 1 (ABCC1) confers resistance to arsenic compounds in human myeloid leukemic HL-60 cells.
Arsenic trioxide (As(2)O(3)) is established as one of the most effective drugs for treatment of patients with acute promyelocytic leukemia, as well as other types of malignant tumors. However, HL-60 cells are resistant to As(2)O(3), and little is known about the underlying resistance mechanism for As(2)O(3) and its biomethylation products, namely, monomethylarsonous acid (MMA(III)) on the treatment of tumors. In the present study, we investigated the molecular mechanisms underlying iAs(III) and its intermediate metabolite MMA(III)-induced anticancer effects in the HL-60 cells. Here, we show that the HL-60 cells exhibit resistance to inorganic iAs(III) (IC(50) = 10 μM), but are relatively sensitive to its intermediate MMA(III) (IC(50) = 3.5 μM). Moreover, we found that the multidrug resistance protein 1 (MRP1), but not MRP2, is expressed in HL-60 cells, which reduced the intracellular arsenic accumulation, and conferred resistance to inorganic iAs(III) and MMA(III). Pretreatment of HL-60 with MK571, an inhibitor of MRP1, significantly increased iAs(III) and MMA(III)-induced cytotoxicity and arsenic accumulations, suggesting that the expression of MRP1/4 may lead to HL-60 cells resistance to trivalent arsenic compounds.
Department of Pharmacology, Toxicology, and Biochemical Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Shi
S
Xu
Yan Fang
YF
Zhang
Micheal W
MW
Carew
Wen Hui
WH
Hao
Jacky Fong Chuen
JF
Loo
Hua
H
Naranmandura
X Chris
XC
Le
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017670:Sodium Compounds / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018053:Arsenites; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009942:Organometallic Compounds; D011422:Propionates; D011804:Quinolines; D017670:Sodium Compounds; C406082:monomethylarsonous acid; C017947:sodium arsenite; C059141:verlukast; C421109:multidrug resistance-associated protein 1