droloxifene and nomegestrol-acetate

To study the modulation of mdr1, glutathione S-transferase Pi (GST pi), topoisomerase II alpha (Topo II alpha) and multidrug resistance-associated protein (MRP) by nomegestrol acetate (NOM) and droloxifene (DRO) in K562 cell line.. Adriamycin (ADM)-resistant K562 (K562/A02) and parental K562 cells were treated with NOM and DRO. The alterations of chemosensitivity to ADM were evaluated by MTT assay, mRNA and protein expression of drug-resistant gene by RT-PCR and immunohistochemistry and accumulation of ADM by flow cytometry (FCM).. Both NOM and DRO markedly enhanced chemosensitivity to ADM of K562/A02 cells. After 20, 10 and 5 mumol/L of NOM or DRO treatment, the chemosensitivities to ADM were increased by 17.7, 15.1 and 5.1 times, respectively in NOM treated cells and by 12.3, 12.9 and 4.0 times, respectively in DRO treated cells. In both the drugs treated cells the accumulation of ADM was increased by 2-3 times. The MDR reversal activity of NOM was similar to that of VRP, but the modulatory action of DRO on K562/A02 cells was weaker than that of VRP at concentration of 20 mumol/L. After 20 mumol/L of NOM treatment, chemosensitivity to ADM of K562 cells was markedly enhanced (P < 0.05). Both NOM and DRO were found to significantly inhibit mdr1 and GST pi expression and increase Topo II alpha expression at the mRNA and protein level. This modulation of gene expression was time dependent and the maximal effects appeared 5 days after drugs treatment. Both NOM and DRO failed to modulate the MRP expression. In K562 cells, NOM and DRO also inhibited GST pi expression (P < 0.05).. Both NOM and DRO could markedly reverse the MDR of K562/A02 cells. The reversal activity of NOM was comparable to that of VRP. Both the drugs could modulate mdr1, GST pi and Topo II alpha expression in a time dependent manner.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; DNA Topoisomerases, Type II; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Estrogen Antagonists; Gene Expression; Genes, MDR; Glutathione Transferase; Humans; K562 Cells; Megestrol; Norpregnadienes; RNA, Messenger; Tamoxifen