Abstract
P-glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance (MDR) in cancer cells. In order to enhance the uptake of chemotherapy drugs, larger amounts of P-gp inhibitors are required. Besides several chemically synthesized P-gp inhibitors, flavonoids as P-gp inhibitors are being investigated, with their advantages including abundance in our daily diet and a low toxicity. The cytotoxicity of daunorubicin (as a substrate of P-gp) to KB/MDR1 cells and the parental KB cells was measured in the presence or absence of flavonoids. A two-dimensional quantitative structure–activity relationship (2D-QSAR) model was built with a high cross-validation coefficient (Q2) value of 0.829. Descriptors including vsurf_DW23, E_sol, Dipole and vsurf_G were determined to be related to the inhibitory activity of flavonoids. The lack of 2,3-double bond, 3′-OH, 4′-OH and the increased number of methoxylated substitutions were shown to be beneficial for the inhibition of P-gp. These results are important for the screening of flavonoids for inhibitory activity on P-gp.
Highlights
P-glycoprotein (P-gp) is a member of the ATP-binding cassette (ABC) family, which is encoded by the ABCB1 gene
It is widely reported that the main cause of the low bioavailability of chemotherapy drugs is related to transport of P-gp [25]
The positive inhibitor elecridar significantly reduced the sensitivity of KB/MDR1 cells to daunorubicin, even to the same level as KB cells
Summary
P-glycoprotein (P-gp) is a member of the ATP-binding cassette (ABC) family, which is encoded by the ABCB1 gene. It is generally believed that the mechanisms of P-gp inhibition mainly comprise four aspects: competitively, non-competitively or allosterically blocking the drug binding site; interfering with the ATP hydrolysis process; altering the integrity of cell membrane lipids; decreasing the P-gp expression [1]. The derivatives of the first-generation inhibitors, dexverapamil and VX710, are termed the second-generation inhibitors. Due to their impact on P450 and drug interaction profiles, these inhibitors were not used clinically [5]. Tetrandrine, and zosuquidar, the third-generation inhibitors, are limited due to their low survival [6]. High-potency and low-toxicity P-gp inhibitors are urgently required for chemotherapy treatment. Compounds from natural products belonging to the fourth-generation P-gp inhibitors are of great significance [7]
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