The combined effects of IL-3 and PSC 833 on daunorubicin- and mitoxantrone cytotoxicity in two growth factor-dependent leukemic cell lines.
In the present study it was investigated whether and by which mechanisms the co-administration of interleukin-3 (IL-3) and the P-glycoprotein blocker PSC 833 can augment mitoxantrone (MX) and daunorubicin (DAU) cytotoxicity in two human growth factor dependent P-glycoprotein (P-gp) positive myeloid leukemic cell lines, Mo-7 and GF-D8. Cytotoxicity was determined in MTT assay. Increased cytotoxicity occurred in Mo-7 cells preincubated with 24h IL-3 followed by 1 h MX (cell survival: 85% +/- 6 vs 68% +/- 2, at 0.05 microM MX, P < 0.005) or DAU (79% +/- 8 vs 62% +/- 9 at 0.8 microg/ml DAU, P < 0.05). Similar results were obtained for the GF-D8 cell line. In this cell line, at 0.5 microM MX the cell survival decreased from 84% +/- 13 to 61% +/- 19 (P < 0.05) and at 5.0 microg/ml DAU from 102% +/- 8 to 69% +/- 5, (P < 0.002). The IL-3 administration did not affect the P-gp and bcl-2 protein expression, cellular MX concentration or MX efflux but coincided with an increased percentage of cells in S-phase and topoisomerase II (topo II)-alpha mRNA and topo II activity especially in the Mo-7 cell line. PSC 833 enhanced DAU cytotoxicity in both cell lines. The administration of IL-3 plus PSC 833 in the Mo-7 cell line resulted in an additive effect on DAU cytotoxicity. At 0.8 microg/ml DAU and 2 microg/ml PSC 833, the percentage surviving cells decreased from 62% +/- 9 in the absence of IL-3 to 37% +/- 3 in the presence of IL-3 (P < 0.01). The additive effect of combined treatment was most pronounced in GF-D8 cells which also had the highest P-gp expression. In contrast, PSC 833 did not modulate the MX effects, irrespective of the presence of IL-3. In summary, the results demonstrate that the combined administration of IL-3 and PSC 833 can enhance the cytotoxic effects of DAU but not MX in these P-gp positive cell lines whereas the effects of MX could be modulated by factors which influence topo II activity.
Asschert
J
J
Department of Internal Medicine, University of Groningen, The Netherlands.
de Vries
E
E
van der Kolk
D
D
Müller
M
M
Vellenga
E
E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000633:toxicity*; D003630:Daunorubicin / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D006801:Humans; D007377:Interleukin-3 / Q000633:toxicity*; D007700:Kinetics; D007938:Leukemia; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000633:toxicity*; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D007377:Interleukin-3; D008942:Mitoxantrone; C070272:valspodar; D003630:Daunorubicin