TY - JOUR
T1 - Thaliblastine, a Plant Alkaloid, Circumvents Multidrug Resistance by Direct Binding to P-Glycoprotein
AU - Chen, Guan
AU - Ramachandran, Cheppail
AU - Krishan, Awtar
PY - 1993/6
Y1 - 1993/6
N2 - The effect of thaliblastine (TBL, NSC-68075), a plant alkaloid, in overcoming 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 μM) reduced the 50% inhibitory dose of ADR (1-h exposure) from 10.8 to 1.4 μM 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 μM, 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.
AB - The effect of thaliblastine (TBL, NSC-68075), a plant alkaloid, in overcoming 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 μM) reduced the 50% inhibitory dose of ADR (1-h exposure) from 10.8 to 1.4 μM 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 μM, 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.
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M3 - Article
C2 - 8098661
AN - SCOPUS:0027322989
VL - 53
SP - 2544
EP - 2547
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -