Role of xenobiotic efflux transporters in resistance to vincristine.
This study characterized interactions between efflux transporters (P-glycoprotein (MDR1) and multidrug resistance associated proteins (MRPs1-3)) and vincristine (VCR), using cell lines with differential transporter expression, and studied effects of P-glycoprotein inhibition on VCR transport and toxicity. Caco2 (express MDR1, MRPs 1-3), LS174T (express MDR1, MRPs 1, 3), and A549 (express MRPs 1-3) cells were used. To study VCR transport (effective permeability, P(eff)), VCR (1-500 nM) was added to the donor chambers of permeable supports containing Caco2 monolayers, and receiving chamber concentrations were measured. Cytotoxicity experiments were conducted with escalating concentrations of VCR in all cell lines. To determine the contribution of MDR1, experiments were also conducted with LY335979, a specific MDR1 inhibitor. VCR P(eff) was 2 x 10(-6)cm/s in Caco2 cells. LY335979 increased P(eff) in a dose dependent manner (up to 7-fold with 1 microM LY335979) in Caco2 cells. Caco2 and LS174T cell viability decreased significantly when co-incubated with both VCR and LY335979 (1 microM) (P<0.05), however this was not observed in A549 cells. In summary, MDR1 plays an important role in VCR efflux; MDR1 inhibition increased VCR P(eff) in Caco2 cells, and increased VCR cytotoxicity in Caco2 and LS174T cells (both express MDR1), but not A549 cells (minimal MDR1 expression). Inhibition of MDR1 may be a viable strategy to overcome VCR resistance in tumors expressing MDR1, however the presence of other efflux transporters should also be considered, as this will influence the success of such strategies.
Huang
Rong S
RS
Department of Pharmacy Practice, Purdue University School of Pharmacy and Pharmaceutical Sciences, W7555 Myers Bldg., Wishard Memorial Hospital, Indianapolis, IN 46202, USA.
Murry
Daryl J
DJ
Foster
David R
DR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001692:Biological Transport; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003986:Dibenzocycloheptenes / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010539:Permeability; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D003986:Dibenzocycloheptenes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011804:Quinolines; D014750:Vincristine; C095179:zosuquidar trihydrochloride