7-O-geranylquercetin contributes to reverse P-gp-mediated adriamycin resistance in breast cancer
Introduction
The efficiency of tumor chemotherapy has been gravely attenuated by the emergence of multidrug resistance (MDR) cancer cells [1,2]. P-glycoprotein (P-gp) is one of the most studied transporters that have been found to be associated with MDR. The over-expression of P-gp in tumor cells often leads to chemotherapy failure [3,4]. Therefore, a series of P-gp inhibitors have been developed to reverse MDR. The first generation inhibitors were not specifically designed for inhibiting MDR and had other pharmacological activities, for example verapamil and cyclosporine A. Because of their low affinity to P-gp, the first generation inhibitors were usually administrated at high doses to reverse MDR in vivo, which led to serious and life-threatening toxicities to the body [4]. The second generation inhibitors including valspodar and biricodar were designed to eliminate non-MDR reverse effects of the first generation. But their affinity towards P-gp was still too low to produce significant inhibition in vivo at tolerable doses [5,6]. Meanwhile, the first and second generation inhibitors interfered with CYP enzymes and affected other transporters to cause drug-drug interactions, resulting in increased concentration levels of the antitumor drugs in the plasma [7]. For instance, in phase I study of co-administration of P-gp inhibitor PSC833 with antitumor drug paclitaxel, PSC 833 decreased paclitaxel clearance by 50%, which could be detrimental to normal tissue [8,9]. The third generation of P-gp inhibitors exhibited an increased specificity to P-gp at concentrations of nanomolar range, and avoided effects on drug metabolic enzymes [6]. However, the phase III clinical trials of some third generation inhibitors, such as tariquidar and zosuquidar, failed due to their toxicity and lack of reversing MDR activities [10]. The current dilemma stressed the requirement to develop new MDR reversal agents.
Quercetin (Q) is a flavonoid existing in many edible fruits and vegetables such as tea, grape, tomato and apple. Q has multiple bioactivities including antioxidant, antiinflammatory, anticancer, antiviral activities [10]. Meanwhile, it can inhibit the expression of P-gp and its coding gene MDR1, and therefore act as a chemo-sensitizer to enhance the cytotoxic effects of chemotherapeutic drugs on MDR cells [11]. Nevertheless, the poor solubility severely restricted its application in clinical setting [12,13]. 7-O-Geranylquercetin (GQ) (Fig. 1) designed and synthesized by our group is a novel alkylated derivative of Q with better lipid solubility and higher antitumor activity in comparison with Q [14]. We have found that the accumulation of GQ in MCF-7 cells was much higher than that of Q [14], which might be the result of inhibition to efflux transporters [15]. However, whether it can reverse the drug resistance of MDR tumor cells still need to be proved.
In this study, we investigated the reversal effect of GQ on the drug resistance of breast cancer cells MCF-7/ADR and explored the possible mechanisms related to P-gp. Our study will provide reference for the research of high-efficient and low-toxic reversal agents against drug resistance in tumor chemotherapy.
Section snippets
Reagents
MDR1 siRNA and PCR primers were designed and synthesized by GenePharma (Shanghai, China). GQ with the purity over 98% was synthesized in our lab according the reported methods [16]. Q was purchased from the Aladdin Industrial Corporation (Shanghai, China). ADR was purchased from Haizheng Pharmaceutical Co., Ltd (Zhejiang, China). RPMI-1640 and fetal bovine serum (FBS) were purchased from Gibco BRL (Gaithersburg, MD, USA). Rhodamine 123 (Rh) and
GQ reversed the resistance of MCF-7/ADR cells to ADR
The cytotoxic activity of GQ to MCF-7 and MCF-7/ADR cells was measured by MTT assay. When MCF-7 and MCF-7/ADR cells were treated with Q or GQ at concentrations no more than 10 μM for 48 h, the cell proliferation rates were all above 90%. The proliferation rates of MCF-7 and MCF-7/ADR cells respectively dropped to 61.59% and 57.16% with the treatment of 20 μM GQ (Fig. 2 A). These results indicated that GQ did not affect cell proliferation at low concentrations (≤10 μM) while it inhibited cell
Discussion
Flavonoids have attracted considerable attention as P-gp inhibitors, since they shared inhibitory activities on P-gp and physiological safety as modulators of MDR [6,25]. Q has been demonstrated to reverse MDR [1] and be safe in human body via a phase I clinical trial [26]. Our previous studies showed that the accumulation of GQ was significantly higher than that of Q in MCF-7 cells, which suggested that GQ might have stronger ability to reverse MDR than Q [14]. The present study tried to
Conclusion
The present study demonstrated that GQ reversed the drug resistance of MCF-7/ADR to ADR by down-regulating the expression of P-gp protein as well as its encoding gene MDR1. In addition, inherent anti-tumor effect of GQ made it more advantageous than other P-gp inhibitors. This indicated that GQ was a potential reversal agent for drug resistance in cancer therapy.
Author contributions
Yuhong Zhen and Xiaohui Kang designed research; Enxia Zhang, Lei Shi, Xin Guo and Ze Liang peformed research; Xiaohui Kang, Hong Xu and Huaxin Wang contributed new analytical tools and reagents; Xiaohong Shu and Shanshan Huang analyzed the data; Jiasi Liu, Jiaxin Zuo and Yuhong Zhen wrote the paper.
Declaration of Competing Interest
The authors declare that they have no conflict of interest.
Acknowledgements
This research was supported by the National Natural Science Foundation of China (No. 21704011), the Natural Science Foundation of Liaoning Province China (No. 20170540233). the Doctoral Scientific Research Foundation of Liaoning Province China (No. 20180540038), the State Key Laboratory of Fine Chemicals (No. KF1713), and the Open Fund of Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education (Dalian Minzu University) China (No. KF2018005).
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These authors contributed equally to this work.