Overcoming MDR by ultrasound-induced hyperthermia and P-glycoprotein modulation.
We assessed the effects of combining ultrasound-induced hyperthermia (USHT) with the P-glycoprotein modulator PSC 833 on cellular retention and cytotoxicity of rhodamine 123 (R123) and doxorubicin in the parent and multidrug resistance (MDR) variants of two human cancer lines. USHT significantly increased cellular uptake of R123 and doxorubicin. Without PSC 833, release of R123 and doxorubicin from both USHT-treated and untreated cells was rapid. As expected, PSC 833 (0.5 microM) only slowed their release into the MDR lines. Interestingly, despite the differences in their starting amounts, PSC 833 was effective in prolonging R123 and doxorubicin release from both USHT-treated and untreated MDR cells. PSC 833 did not augment the cytotoxicity of doxorubicin in parent lines but did cause a significant increase in cytotoxicity of doxorubicin in the MDR lines. However, the combined effect of USHT and PSC 833 on cytotoxicity of doxorubicin far exceeded that produced by USHT or PSC 833 alone.
Liu
Y
Y
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Lillehei
K
K
Cobb
W N
WN
Christians
U
U
Ng
K Y
KY
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D006358:Hot Temperature; D006801:Humans; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014407:Tumor Cells, Cultured; D014465:Ultrasonics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003524:Cyclosporins; D020112:Rhodamine 123; D004317:Doxorubicin; C070272:valspodar