Targeting biliverdin reductase overcomes multidrug resistance in leukemia HL60 cells.
OBJECTIVE
Altered redox status has been reported to play a significant role in the development of multidrug resistance (MDR) in leukemia cells. Human biliverdin reductase (hBVR) has been recently identified as a major cytoprotectant; however, its role in MDR has not been yet investigated. In the present study we evaluated the possible role of hBVR in MDR development in the human HL60 leukemia cell line.


METHODS
The relationship between hBVR and MDR was examined using the drug-sensitive HL60 cells and the drug-resistant HL60 subline, HL60/ADR. A possible chemosensitization by siRNA pre-treatment was also investigated.


RESULTS
We observed that hBVR expression, protein, and enzymatic activity were significantly increased in multidrug-resistant HL60 leukemia cells. We also found that knockdown of hBVR reverses multidrug resistance in resistant leukemic HL60 cells by a ROS-dependent mechanism.


CONCLUSIONS
hBVR plays a pivotal role in the development of multidrug resistance in human HL60 leukemia cells.
M.D., School of Medicine, Konkuk University, Seoul 143-701, Republic of Korea. palelamp@kku.ac.kr.
Sung Su
SS
Kim
Sin
S
Seong
Seong Hyeon
SH
Lim
Sung Young
SY
Kim
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014750:Vincristine; D004317:Doxorubicin; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase
Biliverdin reductase; leukemia; multidrug resistance; reactive oxygen species