Genistein modulates the decreased drug accumulation in non-P-glycoprotein mediated multidrug resistant tumour cells.
In tumour cells the pharmacological basis for multidrug resistance (MDR) often appears to be a reduced cellular cytostatic drug accumulation caused by the drug efflux protein, P-glycoprotein (Pgp MDR), or by other drug transporters (non-Pgp MDR). Here we report the reversal of the decreased daunorubicin (DNR) accumulation in five non-Pgp MDR cell lines (GLC4/ADR, SW-1573/2R120, HT1080/DR4, MCF7/Mitox and HL60/ADR) by genistein. Genistein inhibited the enhanced DNR efflux in the GLC4/ADR cells. In these cells the decreased VP-16 accumulation was also reversed by genistein. Three other (iso)flavonoids biochanin A, apigenin and quercetin also increased the DNR accumulation in the GLC4/ADR cells. In contrast to the effects on non-Pgp MDR cells, 200 microM genistein did not increase the reduced DNR accumulation in three Pgp MDR cell lines (SW-1573/2R160, MCF7/DOX40 and KB8-5) or in the parental cell lines. In conclusion the use of genistein provides a means to probe non-Pgp related drug accumulation defects.
Versantvoort
C H
CH
Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
Schuurhuis
G J
GJ
Pinedo
H M
HM
Eekman
C A
CA
Kuiper
C M
CM
Lankelma
J
J
Broxterman
H J
HJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000502:physiology*; D003630:Daunorubicin / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000493:pharmacokinetics; D004351:Drug Resistance; D005047:Etoposide / Q000493:pharmacokinetics; D019833:Genistein; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007529:Isoflavones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000470:Alkaloids; D002352:Carrier Proteins; D007529:Isoflavones; D008562:Membrane Glycoproteins; D005047:Etoposide; D004317:Doxorubicin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D003630:Daunorubicin