Changes in expression of genes encoding antioxidant enzymes, heme oxygenase-1, Bcl-2, and Bcl-xl and in level of reactive oxygen species in tumor cells resistant to doxorubicin.
The relationship between expression of genes encoding key antioxidant enzymes, heme oxygenase-1, Bcl-2, and Bcl-xl and change in production of reactive oxygen species (ROS) resulting from development of resistance of cancer cells K562, MCF-7, and SKOV-3 to the prooxidant chemotherapeutic agent doxorubicin (DOX) has been studied. Significant increase in mRNA level and activity of Mn-superoxide dismutase (Mn-SOD), catalase, and selenium-dependent glutathione peroxidase-1 (GPx-1) and reduced ROS level was found in resistant K562/DOX and SKVLB cells. In contrast, no change in ROS level was observed in MCF-7/DOX cells in parallel with decrease in Mn-SOD and catalase mRNAs and corresponding activities concurrently with high increase in GPx-1 mRNA and activity. As a result of the development of resistance, a similarity was found between the change in ROS level and the change in ho-1 and bcl-2 gene expression, whereas elevation of bcl-xl gene expression was observed in all three types of resistant cells. Particular features of development of adaptive antioxidant response as well as redox-dependent change in bcl-2 gene expression under formation of DOX resistance of cancer cells of different genesis are discussed.
Kalinina
E V
EV
Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, 119991 Moscow, Russia. kevsan@orc.ru
Chernov
N N
NN
Saprin
A N
AN
Kotova
Ya N
YN
Andreev
Ya A
YA
Solomka
V S
VS
Scherbak
N P
NP
D000975:Antioxidants / Q000032:analysis*; D002374:Catalase / Q000032:analysis / Q000235:genetics; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005979:Glutathione Peroxidase / Q000032:analysis / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017382:Reactive Oxygen Species / Q000032:analysis*; D013482:Superoxide Dismutase / Q000032:analysis / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
D000975:Antioxidants; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D004317:Doxorubicin; D002374:Catalase; D005979:Glutathione Peroxidase; D051547:Heme Oxygenase-1; D013482:Superoxide Dismutase