Macelignan: a new modulator of P-glycoprotein in multidrug-resistant cancer cells.
The effect of macelignan, a phytoestrogen, on P-gp function was investigated using multidrug resistant cancer cells overexpressing P-gp (NCI/ADR-RES) and the fluorescent P-gp substrates, daunorubicin and rhodamine 123. Macelignan (40 microM) increased the cellular accumulation of daunorubicin by approximately threefold in NCI/ADR-RES cells, whereas it did not alter the cellular accumulation of daunorubicin in MCF-7/sensitive cells. Similarly, the presence of macelignan also enhanced significantly (P < 0.05) the cellular accumulation of rhodamine 123 in a concentration-dependent manner in NCI/ADR-RES cells. Furthermore, cancer cells were more susceptible to the cytotoxicity of vinblastine, a P-gp substrate, in the presence of macelignan. Those results suggest that macelignan has inhibitory effects on P-gp mediated cellular efflux. However, P-gp activity did not affect the cellular accumulation of macelignan itself. Taken all together, macelignan was identified as a novel inhibitor of P-gp activity and may be a promising lead compound for the rational design of more efficacious drugs to reverse multidrug resistance in cancer.
College of Pharmacy, Chosun University, Gwangju, Korea.
Young Bin
YB
Im
Ilho
I
Ha
Keon Wook
KW
Kang
Moo-Yeol
MY
Lee
Hyo-Kyung
HK
Han
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000230:Adenocarcinoma; D000704:Analysis of Variance; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D001693:Biological Transport, Active / Q000187:drug effects; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006131:Growth Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D017705:Lignans / Q000493:pharmacokinetics / Q000494:pharmacology*; D048789:Phytoestrogens / Q000493:pharmacokinetics / Q000494:pharmacology; D008517:Phytotherapy; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D014747:Vinblastine / Q000493:pharmacokinetics
D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D006131:Growth Inhibitors; D017705:Lignans; D048789:Phytoestrogens; D020112:Rhodamine 123; D014747:Vinblastine; C502026:macelignan; D003630:Daunorubicin