Faculty Collaboration Database

Thaliblastine, a plant alkaloid, circumvents multidrug resistance by direct binding to P-glycoprotein. Cancer Res 1993 Jun 01;53(11):2544-7

Date

06/01/1993

Pubmed ID

8098661

Scopus ID

2-s2.0-0027322989 (requires institutional sign-in at Scopus site)   37 Citations

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.

Author List

Chen G, Ramachandran C, Krishan A

Author

Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Affinity Labels
Animals
Antineoplastic Agents, Phytogenic
Aporphines
Azides
Benzylisoquinolines
Carrier Proteins
Cell Cycle
DNA, Neoplasm
Dihydropyridines
Doxorubicin
Drug Resistance
Isoquinolines
Leukemia P388
Membrane Glycoproteins
Mice