Enhancement of activities of anti-tumor drugs by dipyridamole against multidrug-resistant human hepatoma PLC/PRF/5 cells.
Dipyridamole (DPM) at 10 microM enhanced the cytotoxicity of anti-tumor drugs, which were associated with multidrug resistance, more in multidrug-resistant human hepatoma PLC/PRF/5 cells (PLC/COL) than in its parental cells (PLC/S). DPM increased, dose-dependently, the intracellular accumulation of [3H]vinblastine in PLC/COL. However, the effect was immediately diminished by its removal from the medium, indicating that DPM needed to be present together with the anti-tumor drugs to enhance the intracellular accumulation of the drugs. DPM inhibited the efflux of [3H]vinblastine from the PLC/COL cells, the binding of [3H]vinblastine to membrane vesicles of PLC/COL, and the binding of [3H]azidopine to P-glycoprotein in the plasma membrane of PLC/COL. Apparently DPM binds to P-glycoprotein and inhibits active efflux. [14C]labeled DPM was quickly incorporated into the cells and the cellular level of [14C]DPM reached a plateau after 5 min. It was slightly higher in PLC/S than in PLC/COL. The cellular [14C]DPM quickly disappeared after its removal from the medium. These results indicate that DPM binds quickly but reversibly to various kinds of cellular proteins including P-glycoprotein and inhibits active efflux of some anti-tumor drugs in multi-drug-resistant tumor cells, resulting in the enhancement of the activities of these drugs.
Tatsuta
T
T
Institute of Applied Microbiology, University of Tokyo, Japan.
Shimizu
K
K
Nishimura
T
T
Suzuki
H
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002474:Cell-Free System; D004176:Dipyridamole / Q000008:administration & dosage*; D004351:Drug Resistance; D004357:Drug Synergism; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D004176:Dipyridamole