Quantification of the expression of multidrug resistance-related genes in human tumour cell lines grown with free doxorubicin or doxorubicin encapsulated in polyisohexylcyanoacrylate nanospheres.
Doxorubicin (dox) encapsulated in polyisohexylcyanoacrylate nanospheres (PIHCA-dox) can circumvent P-glycoprotein-mediated multidrug resistance (MDR). In order to investigate whether this drug formulation is able to select MDR cells in culture in the same way as free doxorubicin does, two human tumour cell lines, K562 and MCF7, were grown with increasing concentrations of either free dox or PIHCA-dox. For both drug formulations and for each selection level, the cell lines were more resistant to free dox than to PIHCA-dox. The MCF7 sublines selected with PIHCA-dox exhibited a higher level of resistance to both doxorubicin formulations than those selected with free doxorubicin. Different levels of overexpression of several genes involved in drug resistance (MDR1, MRP1, BCRP and TOP2alpha) occurred in the resistant variants. MDR1 gene overexpression was consistently higher in free dox-selected cells than in PIHCA-dox-selected cells, while this was the reverse for the BCRP gene. Overexpression of the MRP1 and TOP2alpha genes was also observed in the selected variants. Our results show that several mechanisms may be involved in the acquisition of drug resistance and that drug encapsulation markedly alters or delays these processes.
Laurand
Armelle
A
Laboratoire de Pharmacologie des Agents Anticancéreux, Université Victor Segalen Bordeaux 2, and Institut Bergonié, 229 Cours de l'Argonne, 33076 Bordeaux, France.
Laroche-Clary
Audrey
A
Larrue
Annick
A
Huet
Sylvie
S
Soma
Emilienne
E
Bonnet
Jacques
J
Robert
Jacques
J
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000951:Antigens, Neoplasm; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D003487:Cyanoacrylates / Q000008:administration & dosage* / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000008:administration & dosage*; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression / Q000187:drug effects; D019450:Genes, MDR / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000096:biosynthesis / Q000235:genetics*; D043942:Nanotubes; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; D003487:Cyanoacrylates; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; C116614:ABCG2 protein, human; C057532:polyisohexylcyanoacrylate; C421109:multidrug resistance-associated protein 1