Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979

Int J Cancer. 2003 Jan 1;103(1):121-5. doi: 10.1002/ijc.10792.

Abstract

Our study examines the ability of LY335979 (Zosuquidar trihydrochloride) to modulate 3 distinct ABC transporters that are mechanisms of drug resistance: P-glycoprotein (Pgp, ABCB1), multidrug resistance associated protein (MRP1, ABCC2) and breast cancer resistance protein (BCRP, ABCG2). Pgp-mediated resistance can be modulated by coadministration with the highly potent, selective inhibitor, LY335979. Modulation of resistance by mitoxantrone and vinorelbine, 2 drugs used to treat certain solid tumors, was examined in a 3-day cytotoxicity assay using a panel of HL60 leukemia cell lines or MCF-7 breast cancer transfectants. LY335979, at 0.5 microM, substantially reversed mitoxantrone resistance and fully reversed vinorelbine resistance of Pgp-expressing HL60/Vinc cells. However, LY335979 did not modulate drug resistance in the MRP1-expressing HL60/ADR or drug-sensitive parental HL60 cells. To ascertain if LY335979 modulates BCRP-mediated drug resistance, the sensitivity of 26-fold mitoxantrone resistant, BCRP-transfected MCF-7 cells was evaluated. Addition of 5 microM LY335979, a concentration approximately 100-fold higher than the affinity of Pgp, had little to no effect on the BCRP transfectant. [(125)I]Iodomycin photolabeled Pgp in CEM/VLB(100) membranes and was inhibited by 5 microM LY335979 and GF120918. No photolabeling of MRP or BCRP occurred in H69AR or MCF-7/BCRP membranes, respectively. These results further demonstrate that LY335979 is highly specific for Pgp and does not modulate MRP1- or BCRP-mediated resistance and can be used in combination with mitoxantrone and vinorelbine in tumor cells.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / metabolism*
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Dibenzocycloheptenes / pharmacology*
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple*
  • Drug Resistance, Neoplasm*
  • Female
  • Fetal Viability / drug effects
  • Humans
  • Immunoblotting
  • Neoplasm Proteins / metabolism
  • Quinolines / pharmacology*
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Dibenzocycloheptenes
  • Neoplasm Proteins
  • Quinolines
  • Doxorubicin
  • zosuquidar trihydrochloride