Upregulation of P-glycoprotein in rat hepatoma rho(o) cells: implications for drug-DNA interactions.
Rat hepatoma cells lacking mitochondrial DNA (rho(o) cells) were used as a model system to examine the possible roles of mitochondrial DNA as a target for the DNA-acting anticancer drug Adriamycin (doxorubicin). The rho(o) cells were 45-fold less sensitive to Adriamycin than the parental rho+ cells containing mitochondrial DNA. Other non-DNA-acting drugs also exhibited similar behaviour, and this was shown to be due to a multidrug resistance (MDR) phenotype in the rho(o) cells. This was indicated by confocal microscopy where rho+ cells exhibited thirteenfold higher cellular levels of Adriamycin than rho(o) cells. Upregulation (tenfold) of P-glycoprotein in rho(o) cells was also confirmed by Northern dot blot analysis. Since the MDR phenotype is present in rho(o) cells and upregulation of P-glycoprotein is maintained in these cells, rho(o) cells are not a good model system for drug-DNA studies (where the drug is susceptible to extrusion by P-glycoprotein), and any such results obtained with this system must be treated with considerable caution.
Pillay
V
V
School of Biochemistry, La Trobe University, Bundoora, Australia.
Martinus
R D
RD
Hill
J S
JS
Phillips
D R
DR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000032:analysis / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D004272:DNA, Mitochondrial; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000032:analysis / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D012334:RNA, Neoplasm / Q000032:analysis; D051381:Rats; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; D004272:DNA, Mitochondrial; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D004317:Doxorubicin; C070272:valspodar