title: Thaliblastine, a plant alkaloid, circumvents multidrug resistance by direct binding to P-glycoprotein.
abstract: The effect of thaliblastine (TBL, NSC-68075), a plant alkaloid, in over-coming multidrug resistance was investigated in doxorubicin (ADR)-resistant murine leukemic P388/R-84 cells. In the soft agar clonogenic assay, a nontoxic concentration of TBL (2 microM) reduced the 50% inhibitory dose of ADR (1-h exposure) from 10.8 to 1.4 microM with a dose modification factor of 7.7. Continuous treatment of P388/R-84 cells with ADR and TBL for 24 h further lowered the 50% inhibitory dose from 3.5 to 0.07 microM, the resistance level being decreased from 233-fold in the absence of TBL to 4.7-fold in the presence of TBL as compared to the parental P388 cells. Although ADR or TBL individually had no detectable effects on cell cycle traverse, the combination of the two drugs caused a significant G2 block. Flow cytometric analysis showed that TBL enhanced ADR retention in P388/R-84 cells in a dose- and time-dependent manner. TBL partially blocked the photolabeling of P-glycoprotein with [3H]azidopine, and this blocking effect was further enhanced in combination with ADR. Our results indicate that TBL can reverse multidrug resistance by direct interaction with P-glycoprotein, thereby increasing cellular ADR retention.
authors.affiliation: Department of Radiation Oncology, University of Miami Medical School, Florida 33136.
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: C
authors.initials: C
authors.lastname: Ramachandran
authors.forename: A
authors.initials: A
authors.lastname: Krishan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D001060:Aporphines / Q000378:metabolism* / Q000494:pharmacology; D001386:Azides / Q000378:metabolism; D044182:Benzylisoquinolines; D002352:Carrier Proteins / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D004095:Dihydropyridines / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism* / Q000494:pharmacology; D004351:Drug Resistance; D007546:Isoquinolines / Q000378:metabolism* / Q000494:pharmacology; D007941:Leukemia P388 / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000972:Antineoplastic Agents, Phytogenic; D001060:Aporphines; D001386:Azides; D044182:Benzylisoquinolines; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004095:Dihydropyridines; D007546:Isoquinolines; D008562:Membrane Glycoproteins; C041130:azidopine; D004317:Doxorubicin; C073328:thalicarpine