Differential growth inhibition of isoquinolinesulfonamides H-8 and H-7 towards multidrug-resistant P388 murine leukaemia cells.
The effects of N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide (H-8) and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) on the growth of P388 and its multidrug-resistant (MDR) variants were examined with the objective of assessing the possible changes in cyclic nucleotide-dependent protein kinases and protein kinase C-mediated pathways associated with MDR. H-8, an inhibitor of cyclic nucleotide-dependent protein kinases, inhibited the growth of the parental P388 murine leukaemic cells, but not that of MDR variants up to 200 microM. However the growth of both drug-sensitive and resistant cell lines were uniformly inhibited by H-7. Both the cytotoxic and cytokinetic results revealed that the growth-inhibition by H-8 of P388 cells is mainly due to a blockade of cell-cycle progression rather than due to a killing of cells. The degree of resistance to H-8 was directly proportional to their extent of resistance to vincristine, adriamycin, and 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene)-beta-D-gluco pyr anoside (VP-16) and to that of the expression of P-glycoprotein. These findings raised the possibility that P-glycoprotein might play a role in the cross-resistance to H-8. To test the hypothesis, we examined the effect of H-8 on the binding of 3H-vincristine to membrane fraction isolated from P388/VCR-600 cells and on the enhancement of cytotoxicity to anticancer drugs in MDR cells. H-8 did not have any influences on these reactions. Thus, the cross-resistance to H-8 may be mediated through a mechanism different from an overexpression of P-glycoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)
Ido
M
M
Department of Pediatrics, Mie University School of Medicine, Japan.
Nagao
Y
Y
Higashigawa
M
M
Shibata
T
T
Taniguchi
K
K
Hamazaki
M
M
Sakurai
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D005047:Etoposide / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D007941:Leukemia P388 / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007546:Isoquinolines; D008562:Membrane Glycoproteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D011494:Protein Kinases