MDR hamster cells exhibiting multiple altered gene expression: effects of dexniguldipine-HCl (B859-35), cyclosporin A and buthionine sulfoximine.
An actinomycin D selected, multidrug-resistant (MDR) hamster CHO subline showed strong expression of the P-glycoprotein and sorcin genes together with several other alterations such as a: (i) reduced growth rate, (ii) lowered topoisomerase II, (iii) lowered glutathione-S-transferase-P gene expression, and (iv) the emergence of a 15.5 kDa protein. Besides high resistances to adriamycin, actinomycin D, and vincristine, we observed a lowered sensitivity towards bleomycin, a rather hydrophilic drug usually not involved in P-glycoprotein associated MDR. Moreover, the MDR subline showed a pronounced collateral (enhanced) sensitivity towards the sterically pure dihydropyridine anticancer drug dexniguldipine-HCl (B859-35) preventing its characterization for MDR modulation here. At a non-cytotoxic dose (10 microM) the immunosuppressive cyclic peptide cyclosporin A completely abolished the resistance to vincristine, partially reversed the resistance to teniposide and strongly enhanced the sensitivity towards bleomycin, while not influencing the drug sensitivities of the parental cell line. Buthionine sulfoximine (BSO), an agent depleting cellular glutathione levels, distinctly increased the sensitivity towards teniposide at nontoxic doses (50 microM) exclusively in the MDR subline, while it did not alter vincristine or bleomycin cytotoxicity.
Neumann
M
M
Cold Spring Harbor Laboratory, NY 11724.
Wilisch
A
A
Diddens
H
H
Probst
H
H
Gekeler
V
V
D000228:Adenine Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D015152:Blotting, Northern; D019328:Buthionine Sulfoximine; D016466:CHO Cells; D002135:Calcium-Binding Proteins / Q000235:genetics*; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D004095:Dihydropyridines; D006023:Glycoproteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D001761:Bleomycin; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D014750:Vincristine; D016572:Cyclosporine; D000228:Adenine Phosphoribosyltransferase; D005982:Glutathione Transferase; D004250:DNA Topoisomerases, Type II; C054074:niguldipine