Molecular Mimics of Classic P-Glycoprotein Inhibitors as Multidrug Resistance Suppressors and Their Synergistic Effect on Paclitaxel

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From: PLoS ONE(Vol. 12, Issue 1)
Publisher: Public Library of Science
Document Type: Report
Length: 8,421 words
Lexile Measure: 1490L

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Abstract :

P-glycoprotein (Pgp) is a membrane bound efflux pump spread in a variety of tumor cells and considered as a main component of multidrug resistance (MDR) to chemotherapies. In this work, three groups of compounds (imidazolone, oxazolone and vinyl dipeptide derivatives) were synthesized aiming to develop a molecular framework that effectively suppresses MDR. When tested for their influence on Pgp activity, four compounds coded Cur1-01, Cur1-12V, Curox-1 and Curox-3 significantly decreased remaining ATP concentration indicating Pgp substrate site blocking. On the other hand, Cur-3 and Cur-10 significantly increased remaining ATP concentration, which is indicative of Pgp ATPase inhibition. The cytotoxicity of synthesized compounds was examined against Pgp expressing/highly resistant colorectal cancer cell lines (LS-174T). Compounds Cur-1 and Cur-3 showed considerable cytotoxicity with IC.sub.50 values of 7.6 and 8.9 [mu]M, respectively. Equitoxic combination (at IC.sub.50 concentrations) of PTX and Cur-3 greatly diminished resistant cell clone from 45.7% to 2.5%, albeit with some drop in potency from IC.sub.50 of 7.9 nM to IC.sub.50 of 23.8 nM. On the other hand, combination of PTX and the non-cytotoxic Cur1-12V (10 [mu]M) significantly decreased the IC.sub.50 of PTX to 3.8 nM as well as the resistant fraction to 16.2%. The combination test was confirmed using the same protocol but on another resistant CRC cell line (HCT-116) as we obtained similar results. Both Cur-3 and Cur1-12V (10 [mu]M) significantly increased the cellular entrapment of Pgp probe (doxorubicin) elevating its intracellular concentration from 1.9 pmole/cell to 3.0 and 2.9 pmole/cell, respectively.

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Gale Document Number: GALE|A476889690