Open AccessBBA, a Synthetic Derivative of 23-hydroxybutulinic Acid, Reverses Multidrug Resistance by Inhibiting the Efflux Activity of MRP7 (ABCC10)
Author(s) -
Jun-Jiang Chen,
Atish Patel,
Kamlesh Sodani,
Zhijie Xiao,
Amit K. Tiwari,
Dongmei Zhang,
Yingjie Li,
DongHua Yang,
WenCai Ye,
Sidong Chen,
ZheSheng Chen
Publication year - 2013
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0074573
Subject(s) - efflux , multiple drug resistance , paclitaxel , p glycoprotein , pharmacology , chemistry , drug resistance , biology , medicine , biochemistry , chemotherapy , surgery , microbiology and biotechnology
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 ofPulsatillachinensis . 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 [ 3 H]-paclitaxel by inhibiting the efflux of [ 3 H]-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.