2-Pyrrolinodoxorubicin and its peptide-vectorized form bypass multidrug resistance.
A well-known mechanism leading to the emergence of multidrug-resistant tumor cells is the overexpression of P-glycoprotein, which is capable of lowering intracellular drug concentrations. In the present study, we tested the capability of 2-pyrrolinodoxorubicin (p-DOX), a highly potent derivative of DOX, to bypass multidrug resistance. The accumulation, intracellular distribution and cytotoxicity of p-DOX were tested in two cell lines (K562 and A2780) and their DOX-resistant counterparts (K562/ADR and A2780/ADR). Cellular accumulation and cytotoxicity were dramatically lowered for DOX in resistant cell lines, in comparison with non-resistant cells. In contrast, cellular accumulation, intracellular distribution and cytotoxicity of p-DOX were independent of the nature of the cell lines. The p-DOX showed potent dose-dependent inhibition of cell growth against resistant cells as compared with DOX. After treatment of resistant cells with verapamil, the intracellular levels of DOX were markedly increased and consequent cytotoxicity improved. In contrast, treatment of resistant cells with verapamil did not cause any further enhancement of cell uptake or an increase in the cytotoxic effect of the derivative p-DOX, indicating that the compound bypasses the P-glycoprotein. Finally, we show that vectorization of p-DOX by a peptide vector (SynB3) which has been shown to enhance the brain uptake of DOX and to decrease its heart accumulation does not affect this property. These results indicate that p-DOX and its vectorized form are potent and effective in overcoming multidrug resistance.
Castex
Cédric
C
Synt:em, Parc Scientifique Georges Besse, 30000 Nîmes, France.
Merida
Peggy
P
Blanc
Emmanuelle
E
Clair
Philippe
P
Rees
Anthony R
AR
Temsamani
Jamal
J
D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D001692:Biological Transport; D002352:Carrier Proteins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002467:Cell Nucleus / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D007424:Intracellular Fluid / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D020014:K562 Cells; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D000277:Adjuvants, Pharmaceutic; D002352:Carrier Proteins; D011758:Pyrroles; C098751:AN 204; D004317:Doxorubicin; D014700:Verapamil