Effects of miltefosine on membrane permeability and accumulation of [99mTc]-hexakis-2-methoxyisobutyl isonitrile, 2-[18F]fluoro-2-deoxy-D-glucose, daunorubucin and rhodamine123 in multidrug-resistant and sensitive cells.
Miltefosine is a phospholipid analog that exhibits antineoplastic activity against breast cancer metastases, but its mechanism of action remains uncertain. The aim of this study was to investigate the transport mechanism for the removal of miltefosine and [99mTc]-hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) from multidrug-resistant cells. The P-glycoprotein pump function, cell viability, and 99mTc-MIBI and 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) uptakes were measured in NIH 3T3 (3T3) and NIH 3T3MDR1 G185 (3T3MDR1) mouse fibroblasts and human lymphoid B JY cells. Miltefosine treatment increased the permeability and fluidity of these tumor cells in a concentration-dependent manner. The multidrug-sensitive cells were 3-4 times more sensitive to miltefosine than the multidrug-resistant ones. The extent of 99mTc-MIBI accumulation in the P-glycoprotein-expressing cells increased in the presence of miltefosine, whereas the rhodamine123 and daunorubicin uptakes of the cells did not change significantly. In the 3T3MDR1 cells verapamil reinstated the rhodamine123 and daunorubicin accumulation, but not the 99mTc-MIBI uptake. Cyclosporin A reinstated the uptakes of 99mTc-MIBI, daunorubicin and rhodamine123 by the 3T3MDR1 cells. In a concentration-dependent manner miltefosine decreased the extents of 99mTc-MIBI, rhodamine123, daunorubicin and 18FDG accumulation in the JY and 3T3 cells. Our findings indicate a common transport mechanism for 99mTc-MIBI and miltefosine, which is distinct from that for rhodamine123 and daunorubicin in MDR cells.
Márián
Teréz
T
PET Center, Medical and Health Science Centre, University of Debrecen, Debrecen, Hungary. marian@pet.dote.hu
Balkay
László
L
Trón
Lajos
L
Krasznai
Zoárd T
ZT
Szabó-Péli
Judit
J
Krasznai
Zoltán
Z
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects*; D003630:Daunorubicin / Q000493:pharmacokinetics*; D018432:Drug Resistance, Multiple; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006801:Humans; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D041681:NIH 3T3 Cells; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000493:pharmacokinetics*; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019788:Fluorodeoxyglucose F18; D010767:Phosphorylcholine; D020112:Rhodamine 123; C039128:miltefosine; D017256:Technetium Tc 99m Sestamibi; D014700:Verapamil; D003630:Daunorubicin