Abstract
Iodinated derivatives of verapamil were synthesized and tested as P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) reversal agents. The ability of these compounds to revert MDR was evaluated on daunorubicin-resistant K562 cells, by measuring the intracellular accumulation of rhodamine 123, a fluorescent probe of Pgp transport activity. One of the investigated compounds (16c) was found to be a more potent MDR reversal agent than verapamil and cyclosporin A, used as reference molecules. Further in vitro studies showed that compound 16c restored daunorubicin activity and, when used alone, did not induce cell death, cell cycle perturbation and modification of calcium channel activity in comparison with verapamil.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Animals
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Calcium Channel Blockers / pharmacology
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Calcium Channels, L-Type / metabolism
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Cell Cycle / drug effects
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Cyclosporine / pharmacology
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Daunorubicin / pharmacology
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Drug Resistance, Neoplasm
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Drug Synergism
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Humans
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K562 Cells
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Male
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Myocytes, Cardiac / drug effects
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Myocytes, Cardiac / metabolism
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Rats
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Rats, Wistar
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Rhodamine 123 / pharmacokinetics
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Verapamil / analogs & derivatives*
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Verapamil / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Calcium Channel Blockers
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Calcium Channels, L-Type
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Rhodamine 123
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Cyclosporine
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Verapamil
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Daunorubicin