MDR1 modulators improve the chemotherapy response of human hepatoblastoma to doxorubicin in vitro.
OBJECTIVE
P-glycoprotein, a membrane efflux pump encoded by the MDR1 gene, plays an important role in the development of multidrug resistance in human hepatoblastoma (HB). Chemosensitizers antagonize the efflux action of P-glycoprotein. This study investigates the effects of 3 chemosensitizers (the cyclosporin analogue SDZ PSC 833 (PSC 833), the acridone carboxamide derivative GG 918, and verapamil) on the chemotherapy of HB in vitro.


METHODS
The doxorubicin (DOXO) concentration that produces 50% growth inhibition (IC50) in a HB cell line was determined and additional effects of PSC 833, GG 918, and verapamil were investigated in a cytotoxicity assay. The MDR1 gene expression after treatment was determined in a semiquantitative reverse transcription polymerase chain reaction approach.


RESULTS
The IC50 of DOXO is 2.5 microg/mL, 0.61 microg/mL for DOXO + PSC 833, 1.17 microg/mL for DOXO + verapamil, and 1.47 microg/mL for DOXO + GG 918. In combination with DOXO, cell growth was inhibited 4.1-fold by PSC 833, 2.1-fold by verapamil, and 1.9-fold by GG 918. The MDR1 gene expression was enhanced significantly in all treated cells, with and without modulator.


CONCLUSIONS
MDR1 modulators significantly improve the response of HB to DOXO in vitro. The combination of anticancer agents and MDR1 modulators might be a possible contribution to overcome multidrug resistance in HB.
Warmann
Steven
S
Department of Pediatric Surgery, University of Tübingen, Germany.
Göhring
Gudrun
G
Teichmann
Birgit
B
Geerlings
Heinz
H
Fuchs
Jörg
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines / Q000008:administration & dosage; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D003524:Cyclosporins / Q000008:administration & dosage; D004317:Doxorubicin / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D019450:Genes, MDR / Q000187:drug effects*; D018197:Hepatoblastoma / Q000188:drug therapy*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy*; D044005:Tetrahydroisoquinolines; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000008:administration & dosage
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000903:Antibiotics, Antineoplastic; D003524:Cyclosporins; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; D014700:Verapamil; C083501:Elacridar; C070272:valspodar