Protein kinase C isoenzymes, p53, accumulation of rhodamine 123, glutathione-S-transferase, topoisomerase II and MRP in multidrug resistant cell lines.
We investigated whether the expression of protein kinase C (PKC) isoenzymes, topoisomerase II alpha, II beta, multidrug resistance associated protein (MRP), p53 or the activity of glutathione-S- transferase (GST) are additional factors contributing to the resistance mediated by multidrug resistance gene 1 (mdr 1). the cell lines employed for these studies were human lymphoblastoid CCRF cells selected for resistance with actinomycin D, vincristine and adriamycin, KB-3-1 and matched resistant KB-8-5 and KB-C1 cells (selected with colchicine), and a HeLa cell line, in which the resistance was obtained by transfection with the mdr1-gene. Analysis of PKC isozymes showed that there is no correlation of a specific isoenzyme with resistance, although minor differences in the expression were observed. In vincristine and adriamycin selected cells, topoisomerase II alpha- and II beta-MRNA levels were reduced, and in vincristine selected cells the MRP-mRNA was elevated compared with the sensitive line. In KB cells the levels of topoisomerase II alpha and II beta mRNA were increasing with the resistance. Expression of p53 did not correlate with Pgp levels. In summary, MRP and topoisomerase II may contribute to the mdr1 -mediated resistance in some cell lines, but PKC, p53 and GST seem to be of minor or no importance.
Utz
I
I
Institute of Medical Chemistry and Biochemistry, University of Innsbruck, Austria.
Gekeler
V
V
Ise
W
W
Beck
J
J
Spitaler
M
M
Grunicke
H
H
Hofmann
J
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D015153:Blotting, Western; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins; D018432:Drug Resistance, Multiple; D005982:Glutathione Transferase / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007624:KB Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D000964:Antimetabolites, Antineoplastic; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D005982:Glutathione Transferase; D007527:Isoenzymes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011493:Protein Kinase C; D020112:Rhodamine 123; D012235:Rhodamines; D016159:Tumor Suppressor Protein p53