Modulation of multidrug resistance in human ovarian cancer cell lines by inhibition of P-glycoprotein 170 and PKC isoenzymes with antisense oligonucleotides.
Multidrug resistance in human ovarian carcinoma cell lines is caused by the expression of several related proteins, namely P-glycoprotein 170 (Pgp-170), glutathione S-transferase-pi GST-pi), and thymidylate synthase (TS). These proteins seem to be regulated by a common mechanism in which the expression of protein kinase C (PKC) is involved. Additionally, the function of Pgp-170 is dependent on PKC phosphorylation. However, in ovarian carcinoma cell lines the role of different PKC enzymes responsible for resistance is not quite clear. In the present study we circumvented resistance in taxol resistant human ovarian carcinoma cell lines with antisense oligonucleotides to PKC alpha and PKC beta mRNA and compared the effects with those obtained by Pgp-170 antisense oligonucleotides. We found a significant inhibition of cell number after treatment with Pgp-170 antisense oligonucleotides in combination with taxol. Additionally, resistance could be reversed by treatment with taxol and antisense oligomers to PKC alpha and PKC beta. This shows that regulatory correlations between these proteins exist and that inhibition of the mRNA of PKC alpha and PKC beta isoforms and Pgp-170 can reverse multidrug resistance.
Masanek
Ulrike
U
German Cancer Research Center, Heidelberg, Germany.
Stammler
Gerd
G
Volm
Manfred
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016376:Oligonucleotides, Antisense; C496628:PRKCA protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D017239:Paclitaxel