Resistance reversal effect of a novel taxane compound NPB304 and its collaboration with verapamil / 药学学报
Acta Pharmaceutica Sinica
;
(12): 1279-1288, 2014.
Article
in Chinese
| WPRIM
| ID: wpr-299138
ABSTRACT
The tumor multidrug resistance reversal effect of NPB304, a novel taxane, was studied. MTT assay was used to determine the IC50 of chemotherapy drugs. Western blotting assay was applied to analyze the expression of P-glycoprotein (P-gp). The effect of compounds on the P-gp function and P-gp ATPase activity was determined by rhodamine 123 (Rh123) accumulation assay and analysis kit, respectively. Molecular docking was employed to predict the binding force between compounds and P-gp. Transmembrane transport of NPB304 was analyzed using MDCK II and MDR1-MDCK II cell model. NPB304 displayed multidrug resistance reversal effect on KBV cells and MCF-7/paclitaxel cells, NPB304 collaborative with P-glycoprotein (P-gp) inhibitors verapamil enhanced the reversal activity, specifically, 10 μmol x L(-1) verapamil in combination with paclitaxel reversed resistance by 56.5-fold, while combined with NPB304 increased the reversal fold; NPB304 synergistically increased Rh123 accumulation in the resistant cells when combined with verapamil, and NPB304 at 0-1 μmol x L(-1) enhanced the ATPase activity activated by verapamil was observed. NPB304 existed the hydrophobic interactions with the TM regions of P-gp, and the binding force between NPB304 and the A chain of the TM region was stronger. P-gp ATPase activity assay demonstrated NPB304 at lower concentrations (0-1.5 μmol x L(-1)) could activate the P-gp ATPase, playing a role on inhibition of P-gp function. However, NPB304 did not have an obvious feature of P-gp substrate. NPB304 exerted itself and synergy with verapamil activity on reversing tumor resistance via inhibiting the P-gp function.
Full text:
Available
Index:
WPRIM (Western Pacific)
Main subject:
Pharmacology
/
Biological Transport
/
Verapamil
/
ATP Binding Cassette Transporter, Subfamily B, Member 1
/
Drug Resistance, Multiple
/
Drug Resistance, Neoplasm
/
Rhodamine 123
/
Taxoids
/
Drug Synergism
/
MCF-7 Cells
Type of study:
Prognostic study
Limits:
Humans
Language:
Chinese
Journal:
Acta Pharmaceutica Sinica
Year:
2014
Type:
Article
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