title: Exposure to HIV-protease inhibitors selects for increased expression of P-glycoprotein (ABCB1) in Kaposi's sarcoma cells.
abstract: BACKGROUND
  Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance (MDR) in a fully transformed KS cell line (SLK) was explored.
  
  
  METHODS
  The KS cells were exposed to both acute and chronic treatments of physiological concentrations of different HIV-PIs (indinavir, nelfinavir, atazanavir, ritonavir, or lopinavir), alone or together with doxorubicin. The ABCB1 mRNA and protein expression levels were then assessed by qRT-PCR and western blotting, flow cytometry, and immunofluorescence.
  
  
  RESULTS
  Chronic treatment of SLK cells with one of the five HIV-PIs alone or together resulted in increased resistance to doxorubicin. Co-treatment with one of the HIV-PIs in combination with doxorubicin resulted in a synergistic increase in resistance to doxorubicin, and the degree of resistance was found to correlate with the expression of ABCB1. The SLK cells were also revealed to be cross-resistant to the structurally unrelated drug paclitaxel.
  
  
  CONCLUSIONS
  These studies suggest that ABCB1 is primarily responsible for mediating MDR in SLK cells selected with either HIV-PIs alone or in combination with doxorubicin. Therefore, the roles that ABCB1 and drug cocktails play in mediating MDR in KS in vivo should be evaluated.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Room 2108, Bethesda, MD 20892, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Lucia
authors.forename: R
authors.initials: R
authors.lastname: Anu
authors.forename: M
authors.initials: M
authors.lastname: Handley
authors.forename: J-P
authors.initials: JP
authors.lastname: Gillet
authors.forename: C-P
authors.initials: CP
authors.lastname: Wu
authors.forename: G M
authors.initials: GM
authors.lastname: De Donatis
authors.forename: R
authors.initials: R
authors.lastname: Cauda
authors.forename: M M
authors.initials: MM
authors.lastname: Gottesman
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000069446:Atazanavir Sulfate; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D061466:Lopinavir; D019888:Nelfinavir / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019438:Ritonavir / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000188:drug therapy* / Q000378:metabolism* / Q000821:virology; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011725:Pyridines; D011744:Pyrimidinones; D061466:Lopinavir; D000069446:Atazanavir Sulfate; D019469:Indinavir; D004317:Doxorubicin; D019888:Nelfinavir; D019438:Ritonavir