Ultrasound-Induced hyperthermia increases cellular uptake and cytotoxicity of P-glycoprotein substrates in multi-drug resistant cells.
OBJECTIVE
Localized hyperthermia has been shown previously to augment the cytotoxicity of some lipophilic anticancer drugs. Because many of the substrates for the multi-drug resistance (MDR) transporter P-glycoprotein (P-gp) are lipophilic in nature, studies were conducted to test the hypothesis that hyperthermia induced by ultrasound could also increase cellular uptake and cytotoxicity of P-gp substrates by P-gp-expressing cells.


METHODS
To test this hypothesis, we studied the effects of hyperthermia and ultrasound on cellular accumulation of putative P-gp substrates, rhodamine 123 (R123) and doxorubicin (DOX), and cytotoxicity of DOX in the parent and MDR variants of two human cancer cell lines.


RESULTS
Treatment of cells with hyperthermia or ultrasound (20 min at 41 degrees C) both caused a significant increase over controls (no ultrasound treatment) in R123 and DOX accumulation in the parent and MDR lines of MV522 and KB cells. Ultrasound also substantially increased the antiproliferative effects of DOX in both the parent and MDR variants of MV522 and KB cell lines when compared with controls. Our results also indicated that ultrasound exerted a much greater effect on cellular accumulation of R123 and DOX and cytotoxicity enhancement of DOX in the MDR variants than putative P-gp antagonist such as verapamil.


CONCLUSIONS
The present results point to the potential use of ultrasound-induced hyperthermia as a much safer alternative to P-gp antagonist for reversal of MDR.
Liu
Y
Y
Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262, USA.
Cho
C W
CW
Yan
X
X
Henthorn
T K
TK
Lillehei
K O
KO
Cobb
W N
WN
Ng
K Y
KY
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000633:toxicity; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000378:metabolism / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000528:radiation effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods; D020112:Rhodamine 123 / Q000378:metabolism / Q000633:toxicity; D014407:Tumor Cells, Cultured; D014464:Ultrasonic Therapy; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D020112:Rhodamine 123; D004317:Doxorubicin; D014700:Verapamil