Reversal of P-glycoprotein-mediated multidrug resistance by a synthetic α-aminoxy peptidomimetic.
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.
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. binma@cuhk.edu.hk
Bin
B
Ma
Stella
S
Chai
Na
N
Li
Kenneth K W
KK
To
Winnie Lai Ting
WL
Kan
Dan
D
Yang
Ge
G
Lin
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology*; D057786:Peptidomimetics / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D005456:Fluorescent Dyes; D057786:Peptidomimetics; D020112:Rhodamine 123; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D008239:Lysine