Synergistic interaction between p-glycoprotein modulators and epirubicine on resistant cancer cells.
The macrocyclic lathyrane diterpene latilagascene B, previously isolated from Euphorbia lagascae, was acylated to afford three new diterpene esters, latilagascenes G (1), H (2), and I (3), whose structures were assigned by spectroscopic methods. These acyl derivatives, and the macrocyclic diterpenes of the jatrophane-type, tuckeyanols A (4) and B (5), and euphotuckeyanol (6), isolated from Euphorbia tuckeyana, were tested for P-gp modulating properties on human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines. All the compounds displayed very strong activity. The molecular orbital energies (HOMO and LUMO) of diterpenes 1-6 and 7-13, previously isolated, have also been calculated in order to estimate their probable charge transfer interactions with P-gp. Structure-activity relationships (SAR) are discussed. Furthermore, compounds (1-6) were assayed, in vitro, for their antiproliferative effects in combination with epirubicine and all of them synergistically enhance the effect of the antitumor drug.
Duarte
Noélia
N
iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. das Forças Armadas, 1600-083 Lisbon, Portugal.
Járdánházy
Anett
A
Molnár
Joseph
J
Hilgeroth
Andreas
A
Ferreira
Maria-José U
MJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D015251:Epirubicin / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D015251:Epirubicin