Reversion of P-glycoprotein-mediated multidrug resistance by guggulsterone in multidrug-resistant human cancer cell lines.

Abstract

Multidrug resistance (MDR) presents a serious problem in cancer chemotherapy. Our previous studies have shown that guggulsterone could reverse MDR through inhibiting the function and expression of P-glycoprotein (P-gp). The present study is to further investigate the reversal effects of guggulsterone on MDR in drug-resistant cancer cell lines. The effects of guggulsterone on MDR1mRNA gene expression, intracellular pH, P-gp ATPase activity and glucosylceramide synthase (GCS) expression were assessed by RT-PCR, Laser Scanning Confocal Microscope using the pH-sensitive fluorescent probe BCECF-AM, Pgp-Glo assay system, and flow cytometric technology, respectively. The results showed that guggulsterone ranging from 2.5 to 80 μM significantly promoted the activity of P-gp ATPase in a dose-dependent manner. The intracellular pH of K562/DOX cells was found to be higher than K562 cells. After treatment with guggulsterone (1, 3, 10, 30, 100 μM), intracellular pH of K562/DOX cells decreased in a dose- and time-dependent manner. However, the present study revealed that guggulsterone ranging from 3 to 100 μM had little influence on MDR1 gene expression in K562/DOX cells. Further, the isogenic doxorubicin-resistant MCF-7/DOX cells exhibited a 4.9-fold increase in GCS level as compared with parental MCF-7 human breast cancer cells. After treatment with guggulsterone (0.1, 1, 10 μM) for 48 h, MCF-7/DOX cells were found to have no change of GCS protein expression amount. Guggulsterone might be a potent MDR reversal agent, and its mechanism on MDR needs more research.

• Authors: Hong-Bin Xu, Lu-Zhong Xu, Ling Li, Jun Fu, Xia-Ping Mao
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 694 Issue 1-3 Pg. 39-44 (Nov 05 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 22960326 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Pregnenediones
• pregna-4,17-diene-3,16-dione
• Glucosyltransferases
• ceramide glucosyltransferase

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Cell Line, Tumor
• Drug Resistance, Multiple (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glucosyltransferases (metabolism)
• Humans
• Hydrogen-Ion Concentration
• Intracellular Space (chemistry, drug effects)
• Pregnenediones (pharmacology)