BBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)

Jun-Jiang Chen,Wen-Cai Ye,Dong-Mei Zhang,Si-Dong Chen,Atish Patel,Zhi-Jie Xiao,Amit K Tiwari,Ying-Jie Li,Zhe-Sheng Chen,Dong-Hua Yang,Kamlesh Sodani,Irina V Lebedeva

doi:10.1371/journal.pone.0074573

Abstract

Natural products are frequently used for adjuvant chemotherapy in cancer treatment. 23-O-(1,4'-bipiperidine-1-carbonyl) betulinic acid (BBA) is a synthetic derivative of 23-hydroxybutulinic acid (23-HBA), which is a natural pentacyclic triterpene and the major active constituent of the root of Pulsatilla chinensis . We previously reported that BBA could reverse P-glycoprotein (P-gp/ABCB1)-mediated multidrug resistance (MDR). In the present study, we investigated whether BBA has the potential to reverse multidrug resistance protein 7 (MRP7/ABCC10)-mediated MDR. We found that BBA concentration-dependently enhanced the sensitivity of MRP7-transfected HEK293 cells to paclitaxel, docetaxel and vinblastine. Accumulation and efflux experiments demonstrated that BBA increased the intracellular accumulation of [3H]-paclitaxel by inhibiting the efflux of [3H]-paclitaxel from HEK293/MRP7 cells. In addition, immunoblotting and immunofluorescence analyses indicated no significant alteration of MRP7 protein expression and localization in plasma membranes after treatment with BBA. These results demonstrate that BBA reverses MRP7-mediated MDR through blocking the drug efflux function of MRP7 without affecting the intracellular ATP levels. Our findings suggest that BBA has the potential to be used in combination with conventional chemotherapeutic agents to augment the response to chemotherapy.

Highlights

Chemotherapy is generally used for the treatment of various types of cancers
The MRP subfamily of ATP-binding cassette (ABC) transporters consists of nine members (MRP1-MRP9) and these nine MRP members involved in multidrug resistance (MDR) represent the major share of the 12 members of the C subfamily of ABC transporters [8]
Prior to analyzing the reversal efficacy of BBA, we tested its cytotoxic effect in HEK293/pcDNA3.1 and HEK293/MRP7 cells using MTT assay

Summary

Introduction

Chemotherapy is generally used for the treatment of various types of cancers. Many diverse chemotherapeutic agents can be used to control the growth, multiplication and spread of cancer cells. Resistance to chemotherapeutic drugs is a significant factor that limits the potency of chemotherapy and causes failure of cancer treatment [1]. There are 49 genes in the human genome that encode ABC transporters These transporters have been identified and grouped into seven subfamilies from A to G based on genome sequence similarities [5,6]. ABCB1 ( known as Pglycoprotein/P-gp), ABCC ( known as multidrug resistance protein/MRP) subfamily and ABCG2 ( known as breast cancer resistance protein/BCRP) are considered major players in the development of MDR in cancer cells [4,7]. ABCC10 ( known as multidrug resistance protein 7/MRP7) is one distinct player of MRP subfamily in the development of MDR in cancer cells [9]

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Conclusion