Effect of Calphostin C (PKC inhibitor) on daunorubicin resistance in P388/ADR and HL60/AR cells: reversal of drug resistance possibly via P-glycoprotein.
Calphostin C is a potent and specific inhibitor of protein kinase C (PKC). In this investigation we examined the effect of Calphostin C (without prior exposure to light) on daunorubicin (DNR) accumulation and sensitivity to DNR in multidrug-resistant (MDR) murine leukemia P388/ADR and human myeloid leukemia HL60/AR cells. P388/ADR cells overexpress P-glycoprotein, whereas HL60/AR cells lack any expression of P-glycoprotein (both at mRNA and protein levels). Calphostin C, in a concentration-dependent manner, increased the accumulation of DNR in P388/ADR cells and partially reversed (threefold) the DNR resistance in P388/ADR cells but had no effect on either of the parameters in HL60/AR cells. Calphostin C-induced increased accumulation of DNR in P388/ADR cells was due to increased uptake and decreased efflux of DNR. Furthermore, Calphostin C increased the uptake and decreased the efflux of rhodamine 123 (a substrate for P-gp) in P388/ADR cells but had no such effect in P388 cells. In addition, Calphostin C without exposure to light did not inhibit PKC activity in any of the cell lines studied. Taken together, these data suggest that Calphostin C may reverse drug resistance via P-glycoprotein independently of its effect on PKC activity. Therefore, any data regarding the effect of Calphostin C on the reversal of MDR should be interpreted in the light of these findings.
Gupta
S
S
Division of Basic and Clinical Immunology, University of California, Irvine 92717.
Patel
K
K
Singh
H
H
Gollapudi
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002352:Carrier Proteins / Q000502:physiology*; D004396:Coloring Agents / Q000493:pharmacokinetics; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D009281:Naphthalenes; D011083:Polycyclic Compounds / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002352:Carrier Proteins; D004396:Coloring Agents; D008562:Membrane Glycoproteins; D009281:Naphthalenes; D011083:Polycyclic Compounds; D012235:Rhodamines; D020112:Rhodamine 123; D011493:Protein Kinase C; C058819:calphostin C; D003630:Daunorubicin