title: Inhibition of MDR1 activity in vitro by a novel class of diltiazem analogues: toward new candidates.
abstract: The reversal of multidrug resistance by 22 molecules [8-aryl-8-hydroxy-5-R'-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1a-i) and 8-aryl-8-alkoxy-5-methyl-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (2a-m)] related to myocardial-calcium-channel-modulator diltiazem was studied in multidrug resistant A2780/DX3 and their sensitive counterpart A2780 cells. MTT, cytofluorimetry assays, and fluorescence microscopy analyses were used to define activity and accumulation of doxorubicin with or without the diltiazem-like modulators. Of the 22 molecules, 1a, 2f, 2g, and 2m were able to overcome the established criteria for the selection in A2780/DX3 cells (IC(50) reduction > or = 25%), but only 2f, 2g, and 2m caused a significant increase of intracellular accumulation of doxorubicin. In conclusion, experiments lead to the identification of three diltiazem-like molecules able to increase the intracellular accumulation of doxorubicin by inhibiting the MDR1 function, thus potentiating its antiproliferative activity in multidrug resistant A2780/DX3 cells.
authors.affiliation: Istituto Nazionale per la Ricerca sul Cancro, S.C. Terapia Immunologica, L.go R. Benzi 10, 16132 Genova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Viale
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cordazzo
authors.forename: Barbara
authors.initials: B
authors.lastname: Cosimelli
authors.forename: Daniela
authors.initials: D
authors.lastname: de Totero
authors.forename: Patrizio
authors.initials: P
authors.lastname: Castagnola
authors.forename: Cinzia
authors.initials: C
authors.lastname: Aiello
authors.forename: Elda
authors.initials: E
authors.lastname: Severi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Petrillo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cianfriglia
authors.forename: Domenico
authors.initials: D
authors.lastname: Spinelli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D066298:In Vitro Techniques; D008856:Microscopy, Fluorescence
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004317:Doxorubicin; D004110:Diltiazem