Abstract
P-glycoprotein (P-gp) effluxes lots of chemotherapeutic agents and leads to multidrug resistance (MDR) in cancer treatments. The development of P-gp inhibitors from natural products provide a potential strategy for the beneficial clinical outcomes. This study aimed to evaluate the effects of the natural flavonoid taxifolin, luteolin, (−)-gallocatechin, and (−)-catechin on human P-gp activity. The kinetic interactions and underlying mechanisms of taxifolin-mediated transporter inhibition were further investigated. The transporter inhibition ability was evaluated in human P-gp stable expression cells (ABCB1/Flp-InTM-293) by calcein-AM uptake assays. The kinetics study for P-gp inhibition was evaluated by doxorubicin and rhodamine123 efflux assays. The MDR reversal ability of taxifolin were performed by SRB assays to detect the cell viability in sensitive cancer cell line (HeLaS3), and resistant cancer cell line (KB-vin). Cell cycle analysis and ABCB1 real-time RT-PCR were used for mechanical exploration. The results demonstrated that taxifolin decreased ABCB1 expression in a concentration-dependent manner. The function of P-gp was inhibited by taxifolin through uncompetitive inhibition of rhodamine 123 and doxorubicin efflux. The combination of taxifolin significantly resensitized MDR cancer cells to chemotherapeutic agents. These results suggested that taxifolin may be considered as a potential P-gp modulator for synergistic treatment of MDR cancers.
Highlights
Multidrug resistance (MDR) is one of the main causes of cancer chemotherapy failure
The binding of taxifolin stimulated the P-gp ATPase activity, causing the inhibition of P-gp efflux function. These results suggested that taxifolin belongs to a Class has been found to bind at ATP-binding site of heat shock protein 90 (Hsp90) [16]
Dulbecco’s modified Eagle’s medium (DMEM), RPMI-1640 medium, 0.25% Trypsin-EDTA, phosphate-buffered saline (PBS) and fetal bovine serum (FBS) were all obtained from Thermo Fisher
Summary
Multidrug resistance (MDR) is one of the main causes of cancer chemotherapy failure. The most recognized mechanism of resistance is the decreased accumulation of drugs due to increased efflux by ATP-binding cassette (ABC) efflux transporters [1]. Among the ABC transporters, P-glycoprotein (P-gp), encoded by ABCB1 gene, is the main efflux transporter for a variety of chemotherapeutic agents. Overexpression of P-gp in cancer cells has been associated with the MDR phenomenon [3]. The development of P-gp inhibitors is considered as a promising strategy to overcome MDR cancer. A large number of P-gp inhibitors have been developed, the unexpected systemic toxicities and pharmacokinetic interactions raised serious concerns regarding clinical benefits [4]. The development of fourth generation P-gp inhibitors with safety advantages from natural products has gradually been valued
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