Alleviation of the drug-resistant phenotype in idarubicin and cytosine arabinoside double-resistant acute myeloid leukemia cells by indomethacin.
Chemoresistance to anticancer drugs is a major issue in the successful treatment of acute myeloid leukemia (AML). In this study, we developed an AML cell line (AML-2/IDAC) that is resistant to treatment with a combination of idarubicin and cytosine arabinoside (Id/AraC) by chronic exposure for more than 3 months. We then investigated the ability of indomethacin to alleviate the chemoresistance of AML-2/IDAC cells. Treatment with indomethacin alone induced growth arrest, but not the death of AML-2/IDAC cells. However, when AML-2/IDAC cells were treated with combinations of indomethacin and Id/AraC, the cell death and apoptosis rate of AML-2/IDAC cells were significantly increased in a dose- and time-dependent manner. The combined treatment with indomethacin and Id/AraC caused the collapse of the mitochondrial membrane potential and was also demonstrated to enhance the activities of caspase-3 and -8 in AML-2/IDAC cells. Furthermore, indomethacin down-regulated expression of the ABCA3 and MRP1 genes, which were over-expressed in AML-2/IDAC cells. Taken together, the results of this study suggest that indomethacin can be used to increase the therapeutic potential against drug-resistant AML when combined with anti-leukemic drugs.
Song
Ju Han
JH
School of Life Sciences and Biotechnology, Korea University, Seoul 136-713, Korea.
Kim
Seung Hyun
SH
Kim
Hyeoung-Joon
HJ
Hwang
Seung Yong
SY
Kim
Tae Sung
TS
D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015255:Idarubicin / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010641:Phenotype
D018528:ATP-Binding Cassette Transporters; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D003561:Cytarabine; D015255:Idarubicin; D007213:Indomethacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C441524:ABCA3 protein, human; C421109:multidrug resistance-associated protein 1