Differential effect of HIV-1 protease inhibitors on P-glycoprotein function in multidrug-resistant variants of the human CD4+ T lymphoblastoid CEM cell line.
BACKGROUND
P-glycoprotein causing multidrug resistance (MDR) and limiting the efficacy of antineoplastic drugs and protease inhibitors (PIs) is expressed in human CD4+ T lymphocytes, one of the main targets of HIV, in a range of pharmacological barriers and at varying degrees in non-Hodgkin's lymphoma and Kaposi's sarcoma.


METHODS
The differential effect of PIs on P-glycoprotein function was studied by measuring drug efflux inhibition, MDR-reversing ability and MAb UIC2 epitope modulation in MDR variants of the human T lymphoblastoid CEM cell line.


RESULTS
The treatment of MDR cells with PIs induces different UIC2 epitope modulations indicating a differential recognition and binding of these antiviral drugs by MDR1 P-glycoprotein. In fact, ritonavir, saquinavir and indinavir act differently to the P-glycoprotein blocker in CEM-VBL10 cells. The MDR level of these cells was markedly affected by ritonavir and saquinavir in the order, while the PI indinavir does not seem to compete with the P-glycoprotein drug transport function. In CEM-VBL100 cells, expressing a very high number of P-glycoprotein molecules, only ritonavir acts as an efficient drug efflux inhibitor and MDR-reversing agent.


CONCLUSIONS
The HIV-1 PIs ritonavir and saquinavir even at different levels act as genuine P-glycoprotein substrates by inhibiting dye substrate efflux, modulating UIC2 epitope and reversing drug resistance. Conversely, at least in the in vitro system used in the present study, the PI indinavir does not significantly alter P-glycoprotein drug transport activities and function.
Dupuis
Maria Luisa
ML
Laboratorio di Immunologia, Istituto Superiore di Sanità, Rome, Italy. mldupuis@iss.it
Tombesi
Marina
M
Sabatini
Marco
M
Cianfriglia
Maurizio
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D016525:Antigenic Modulation / Q000187:drug effects* / Q000276:immunology; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D001896:Boron Compounds / Q000493:pharmacokinetics; D015496:CD4-Positive T-Lymphocytes / Q000145:classification / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000276:immunology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005982:Glutathione Transferase / Q000187:drug effects / Q000378:metabolism; D016333:HIV Protease / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000276:immunology / Q000494:pharmacology; D011487:Protein Conformation / Q000187:drug effects; D019438:Ritonavir / Q000276:immunology / Q000494:pharmacology; D019258:Saquinavir / Q000276:immunology / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001896:Boron Compounds; D017320:HIV Protease Inhibitors; D014747:Vinblastine; D019469:Indinavir; D004317:Doxorubicin; D005982:Glutathione Transferase; D016333:HIV Protease; D019258:Saquinavir; D019438:Ritonavir