Reversal of P-glycoprotein-mediated multidrug resistance by a synthetic α-aminoxy peptidomimetic

Bin Ma, Stella Chai, Na Li, Kenneth K.W. To, Winnie Lai Ting Kan, Dan Yang, Ge Lin

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


The lack of selectivity and adequate potency of currently known P-glycoprotein (P-gp) inhibitors obscured their further development for clinical use to circumvent P-gp-mediated multidrug resistance (MDR), which necessitates the investigation of novel ones with higher potency and better specificity. The present study investigated the reversal effect of a new synthetic α-aminoxy lysine-peptidomimetic (Lys-P) on P-gp-mediated MDR. Effects of Lys-P on cytotoxicity of P-gp substrate doxorubicin (Dox) and intracellular accumulation of another P-gp substrate rhodamine 123 were examined in HEK293 cells. Its interaction mechanism and effect on P-gp expression were further investigated using ATPase assay and Western blot in Caco-2 cells, respectively. Lys-P restored the cytotoxicity of Dox toward the resistant MDR1-transfected HEK293 and MCF-7 TX400 cells without affecting their corresponding parental cells. It also significantly increased intracellular accumulation (21-fold) of rhodamine 123 in HEK293 MDR1 cells. Further mechanistic studies demonstrated that in the Caco-2 cell monolayer model, Lys-P abolished the P-gp-mediated efflux of Dox due to uncompetitive inhibition of P-gp ATPase without altering P-gp expression. Our findings demonstrated that Lys-P can be used as a promising lead compound for further development into selective and efficient MDR reversing agents for combination use with P-gp substrate drugs in cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)33-39
Number of pages7
JournalInternational journal of pharmaceutics
Issue number1-2
StatePublished - Mar 15 2012

Bibliographical note

Funding Information:
This work was supported by Hong Kong Research Grants Council Central Allocation fund ( HKU 2/06C ) and Chinese University of Hong Kong Direct Grant ( 2041542 ).


  • Lysine- peptidomimetic
  • Multidrug resistance reversal
  • P-glycoprotein inhibitor


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