A 20(S)-protopanoxadiol derivative overcomes multi-drug resistance by antagonizing ATP-binding cassette subfamily B member 1 transporter function.

Gang Chen,Qin Xu,Xu Wang,Lihong Hu,Meng Xiao,Junhua Liu,Li Mao,Wantao Chen

doi:10.18632/oncotarget.7011

Abstract

In cancer cells, failure of chemotherapy is often caused by the ATP-binding cassette subfamily B member 1 (ABCB1), and few drugs have been successfully developed to overcome ABCB1-mediated multi-drug resistance (MDR). To suppress ABCB1 activity, we previously designed and synthesized a new series of derivatives based on 20(S)-protopanoxadiol (PPD). In the present study, we investigated the role of PPD derivatives in the function of ABC transporters. Non-toxic concentrations of the PPD derivative PPD12 sensitized ABCB1-overexpressing cells to their anti-cancer substrates better than either the parental PPD or inactive PPD11. PPD12 increased intracellular accumulation of adriamycin and rhodamine123 in resistant cancer cells. Although PPD12 did not suppress the expression of ABCB1 mRNA or protein, it stimulated the activity of ABCB1 ATPase. Because PPD12 is a competitive inhibitor, it was predicted to bind to the large hydrophobic cavity of homology-modeled human ABCB1. PPD12 also enhanced the efficacy of adriamycin against ABCB1-overexpressing KB/VCR xenografts in nude mice. In conclusion, PPD12 enhances the efficacy of substrate drugs in ABCB1-overexpressing cancer cells. These findings suggest that a combination therapy consisting of PPD12 with conventional chemotherapeutic agents may be an effective treatment for ABCB1-mediated MDR cancer patients.

Highlights

Multi-drug resistance (MDR), which is the resistance to anti-cancer chemotherapeutic agents with different targets, reduces the efficacy of cancer chemotherapy [1, 2]
There are several different ABC transporters associated with the development of MDR, adenine triphosphate (ATP)-binding cassette subfamily B member 1 (ABCB1), ABCG2 and ABCC1 are the most important [6,7,8,9,10]
We demonstrate that PPD12, compared to its parental compound PPD and inactive compound PPD11, sensitizes ABCB1-medidated MDR cancer cells to chemotherapeutic agents in vitro and in vivo

Summary

Introduction

Multi-drug resistance (MDR), which is the resistance to anti-cancer chemotherapeutic agents with different targets, reduces the efficacy of cancer chemotherapy [1, 2]. There are a variety mechanisms underlying MDR in cancer, including the induction of anti-apoptotic machinery, increased drug efflux, and reduced drug uptake. Among these causes, over-expression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is the most common reason for MDR in various types of tumors [3,4,5]. There are several different ABC transporters associated with the development of MDR, ABCB1, ABCG2 and ABCC1 are the most important [6,7,8,9,10]. ABCB1 expression is a marker of chemo-resistance and decreased survival in leukemia, lymphoma, osteosarcoma, small-cell lung cancer, ovarian cancer, breast cancer, and other malignancies [14]

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Conclusion