Targeting P-glycoprotein: Investigation of piperine analogs for overcoming drug resistance in cancer

Abstract

P-glycoprotein (P-gp) is a drug transporter that effluxes chemotherapeutic drugs and is implicated in the development of resistance of cancer cells to chemotherapeutic drugs. To date, no drug has been approved to inhibit P-gp and restore chemotherapy efficacy. Moreover, majority of the reported inhibitors have high molecular weight and complex structures, making it difficult to understand the basic structural requirement for P-gp inhibition. In this study, two structurally simple, low molecular weight piperine analogs Pip1 and Pip2 were designed and found to better interact with P-gp than piperine in silico. A one step, acid-amine coupling reaction between piperic acid and 6,7-dimethoxytetrahydroisoquinoline or 2-(3,4-dimethoxyphenyl)ethylamine afforded Pip1 and Pip2, respectively. In vitro testing in drug resistant P-gp overexpressing KB (cervical) and SW480 (colon) cancer cells showed that both analogs, when co-administered with vincristine, colchicine or paclitaxel were able to reverse the resistance. Moreover, accumulation of P-gp substrate (rhodamine 123) in the resistant cells, a result of alteration of the P-gp efflux, was also observed. These investigations suggest that the natural product analog – Pip1 ((2E,4E)-5-(benzo[d][1,3]dioxol-5-yl)-1-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)penta-2,4-dien-1-one) – is superior to piperine and could inhibit P-gp function. Further studies are required to explore the full potential of Pip1 in treating drug resistant cancer.

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

“…Another example is piperine, an alkaloid and major component of black pepper (Piper nigrum) and long pepper (Piper longum). This compound exhibits P-GP inhibitory activity, and also antitumoral, antioxidant, antimicrobial, and hepatoprotective functions (191). Other flavonoids such as luteolin and casticin have been shown to be active on glioma stem-like cells (192,193).…”

Effective Targeting of Colon Cancer Cells with Piperine Natural Anticancer Prodrug Using Functionalized Clusters of Hydroxyapatite Nanoparticles

“…Importantly, Pip is considered a potent inhibitor of p-glycoprotein (P-GP), which results in the inhibition of multidrug resistance in cancer [55]. Recently, Pip analogs have been developed to target P-GP and overcome drug resistance in cancer [56]. Interestingly, Pip has shown selective anticancer effects on cancer cells compared to normal cells [53].…”

Lipid-Uptake Pathways and Lipid-Protein interactions in P-glycoprotein Revealed by Coarse-Grained Molecular Dynamics Simulations

“…P-gp is one of the best characterized and most studied ABC transporters [11] [43]. Its broad substrate-specificity allows for the transport of many, chemically diverse molecules [44]- [46], and to date, several studies have suggested poly-specific drug binding sites in the cavity of P-gp [ [52].…”

“…The characterization of lipid binding sites and lipid-uptake mechanisms in P-gp is relevant for a better understanding of drug binding to P-gp and other ABC transporters that are capable of translocating lipids [49] [54]. In addition, direct interaction between P-gp and lipid-based molecules as miltefosine and edelfosine, lipidbased anticancer drug molecules, has been previously described [4][42] [52]. Towards this aim, we perform CG MD simulations in equilibrium to explore how lipid molecules access the cavity of P-gp.…”