Target Validation Information
Target ID T93062
Target Name Multidrug resistance protein 3
Target Type
Discontinued
Drug Potency against Target LY335979 Drug Info IC50 = 59 nM [552293]
Action against Disease Model LY335979 LY335979 could effectively block Pgp function on isolated CD56(+) lymphocytes (IC(50) = 1.2 nM) or CD56(+) lymphocytes in whole blood (IC(50) = 174 nM) [552255] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations We previously established that multicellular ovarian cancer spheroids develop intrinsic multidrug resistance with the appearance of quiescent cell areas. p27 protein is a determinant of such resistance. However, the precise molecular basis of such resistance remains unknown. We demonstrated herein that these multicellular ovarian cancer spheroids expressed high levels of p27and P-gp protein. Compared with monolayer cells, there is a significant increase in the resistance of spheroids cells to anticancer reagent Taxol. Antisense oligodeoxynucleotide not only mediated down-regulation of p27, but also P-gp expression in multicellular spheroids. Selective small interfering RNAs (siRNA) of P-gp with MDR1-targeted short hairpin RNAs (shRNA) expression vector sensitized the cells to Taxol. These results suggest that both p27 and P-gp can modulate Taxol sensitivity respectively, while p27 requires P-gp for its full function. Increased P-gp protein expression through p27mediation is one of the major mechanisms of Taxol resistance in ovarian cancer multicellular spheroids. [552293]
References
Ref 552293Three-dimensional quantitative structure-activity relationships of inhibitors of P-glycoprotein. Mol Pharmacol. 2002 May;61(5):964-73.
Ref 552255Modulation by LY335979 of P-glycoprotein function in multidrug-resistant cell lines and human natural killer cells. Biochem Pharmacol. 2001 Jun 1;61(11):1393-9.

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