bba, a synthetic derivative of 23-hydroxybutulinic acid, reverses multidrug resistance by inhibiting the efflux activity of MRP7 (ABCC10).
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 Pulsatillachinensis. 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.
Guangdong Key Laboratory for Molecular Epidemiology, School of Public Health, Guangdong Pharmaceutical University, Guangzhou, China ; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York, United States of America.
Jun-Jiang
JJ
Chen
Atish
A
Patel
Kamlesh
K
Sodani
Zhi-Jie
ZJ
Xiao
Amit K
AK
Tiwari
Dong-Mei
DM
Zhang
Ying-Jie
YJ
Li
Dong-Hua
DH
Yang
Wen-Cai
WC
Ye
Si-Dong
SD
Chen
Zhe-Sheng
ZS
Chen
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D021381:Protein Transport / Q000187:drug effects; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D000094062:Betulinic Acid
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D000094062:Betulinic Acid; C513055:ABCB1 protein, human; C421142:ABCC10 protein, human