The effects of jatrophane derivatives on the reversion of MDR1- and MRP-mediated multidrug resistance in the MDA-MB-231 (HTB-26) cell line.
Multidrug resistance (MDR) of cancer cells can be the result of a variety of mechanisms that are not completely understood. One of the most significant among them concerns altered membrane transport in tumor cells, often referred to as typical or classic MDR. This mechanism is related to the overexpression of a variety of proteins, that belong to the super family of ABC transporters. The aim or this study was to look for new effective modulators of MDR1 and multidrug resistance-associated protein (MRP) transporters. Ten diterpenes based on the jatrophane skeleton, including rearranged polycyclic derivatives, were studied on the MDA-MB-231 (HTB-26) human breast cancer cell line. The majority of those compounds were able to strongly enhance the rhodamine 123 accumulation of the human MDR1 gene transfected mouse lymphoma cell line, as previously described. In the present study, the MDR reversal of the same jatrophanes on MDR1- and MRP- mediated resistance of human breast cancer cells is reported. These cells simultaneously express MDR1 and MRP proteins when identified by monoclonal antibodies. However, in a functional assay, where rhodamine 123 accumulation was measured and verapamil was the traditional positive control, only MRP was active, while MDR1 was inactive. Carboxyfluorescein served as a substrate for MRP-mediated drug efflux, and indomethacine was the positive control used as an inhibitor of MRP in the flow cytometric experiments. The effectivity of various jatrophanes was different on the carboxyfluorescein efflux inhibition of the human breast cancer cells. These results may have importance in the planning of a new type of combination chemotherapy.
Ferreira
Maria-José U
MJ
Centro de Estudos de Ciencias Farmacêuticas, Faculdade de Farmícia da Universidade de Lisbon, Av. das Forças Armadas, 1600-083 Lisbon, Portugal.
Gyémánt
Nora
N
Madureira
Ana Margarida
AM
Tanaka
Masaru
M
Koós
Kitti
K
Didziapetris
Remigijus
R
Molnár
Joseph
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004224:Diterpenes / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D028481:Euphorbia / Q000737:chemistry; D005452:Fluoresceins / Q000493:pharmacokinetics; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020112:Rhodamine 123 / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004224:Diterpenes; D005452:Fluoresceins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D020112:Rhodamine 123; C024098:6-carboxyfluorescein