Cellular and biochemical characterization of VX-710 as a chemosensitizer: reversal of P-glycoprotein-mediated multidrug resistance in vitro

Anticancer Drugs. 1997 Feb;8(2):125-40. doi: 10.1097/00001813-199702000-00004.


VX-710 or (S)-N[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-piperidine-2-carboxylic acid 1,7-bis(3-pyridyl)-4-heptyl ester, a novel non-macrocyclic ligand of the FK506-binding protein FKBP12, was evaluated for its ability to reverse P-glycoprotein-mediated multidrug resistance in vitro. VX-710 at 0.5-5 microM restored sensitivity of a variety of multidrug resistant cells to the cytotoxic action of doxorubicin, vincristine, etoposide or paclitaxel, including drug-selected human myeloma and epithelial carcinoma cells, and human MDR1 cDNA-transfected mouse leukemia and fibroblast cells. Uptake experiments showed that VX-710 at 0.5-2.5 microM fully restored intracellular accumulation of [14C]doxorubicin in multidrug resistant cells, suggesting that VX-710 inhibits the drug efflux activity of P-glycoprotein. VX-710 effectively inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine or [125I]iodoaryl azidoprazosin with EC50 values of 0.75 and 0.55 microM. Moreover, P-glycoprotein was specifically labeled by a tritiated photoaffinity analog of VX-710 and unlabeled VX-710 inhibited analog binding with an EC50 of 0.75 microM. VX-710 also stimulated the vanadate-inhibitable P-glycoprotein ATPase activity 2- to 3-fold in a concentration-dependent manner with an apparent k(a) of 0.1 microM. These data indicate that a direct, high-affinity interaction of VX-710 with P-glycoprotein prevents efflux of cytotoxic drugs by the MDR1 gene product in multidrug resistant tumor cells.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / physiology*
  • Adenosine Triphosphatases / drug effects
  • Adenosine Triphosphatases / metabolism
  • Affinity Labels
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / metabolism
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple / physiology*
  • Drug Resistance, Neoplasm / physiology
  • Etoposide / pharmacology
  • Heat-Shock Proteins / drug effects
  • Heat-Shock Proteins / metabolism
  • Humans
  • Mice
  • Paclitaxel / pharmacology
  • Piperidines / pharmacology*
  • Pyridines / pharmacology*
  • Tacrolimus Binding Proteins
  • Transfection
  • Tumor Cells, Cultured
  • Vincristine / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Affinity Labels
  • Antineoplastic Agents
  • Carrier Proteins
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Piperidines
  • Pyridines
  • biricodar
  • Vincristine
  • Etoposide
  • Doxorubicin
  • Adenosine Triphosphatases
  • Tacrolimus Binding Proteins
  • Paclitaxel