Abstract
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 language | English (US) |
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Pages (from-to) | 33-39 |
Number of pages | 7 |
Journal | International journal of pharmaceutics |
Volume | 424 |
Issue number | 1-2 |
DOIs | |
State | Published - Mar 15 2012 |
Externally published | Yes |
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 ).
Keywords
- Lysine- peptidomimetic
- Multidrug resistance reversal
- P-glycoprotein inhibitor