P-glycoprotein-mediated multidrug resistance is modulated by pretreatment with chemosensitizers in HCT-8 carcinoma cells in vitro.
The effects of pretreatment with the multidrug resistance (MDR) modulators verapamil (VPM), tamoxifen (TMX), cyclosporin A (CsA), and SDZ PSC833 (PSC) on drug sensitivity of the P-glycoprotein (Pgp) expressing human ileocecal carcinoma cell line HCT-8 is described. Following pretreatment of 2, 16 and 48 h with the individual modulators, rhodamine 123 efflux (RHO), transepithelial vinblastine transport (VIN) across treated HCT-8 monolayers, and chemosensitivity to doxorubicin (DOX) were determined and compared to Pgp protein expression and phosphorylation. After 2 h, VPM, TMX, CsA and PSC inhibited RHO efflux and VIN transport and increased the chemosensitivity of HCT-8 to DOX significantly. Prolonged exposure failed to further increase inhibition of Pgp-mediated transport, but in contrast maximized phosphorylation of Pgp (16 h) and Pgp protein expression (48 h), respectively.
Haberl
I
I
Department of Surgery, University of Vienna, Vienna, Austria.
Swatonek
H
H
Schaufler
K
K
Ulsperger
E
E
Wenzl
E
E
Theyer
G
G
Hamilton
G
G
Thalhammer
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D000230:Adenocarcinoma; D001692:Biological Transport / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007078:Ileal Neoplasms; D007080:Ileocecal Valve; D007700:Kinetics; D010766:Phosphorylation; D020112:Rhodamine 123; D012235:Rhodamines; D013629:Tamoxifen / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*; D014747:Vinblastine / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D012235:Rhodamines; D013629:Tamoxifen; D020112:Rhodamine 123; D014747:Vinblastine; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; D013755:Tetradecanoylphorbol Acetate; C070272:valspodar