title: 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.affiliation: Department of Clinical Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China. xuhongbin119@yahoo.cn
authors.forename: Hong-Bin
authors.initials: HB
authors.lastname: Xu
authors.forename: Lu-Zhong
authors.initials: LZ
authors.lastname: Xu
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Fu
authors.forename: Xia-Ping
authors.initials: XP
authors.lastname: Mao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005964:Glucosyltransferases / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D042541:Intracellular Space / Q000737:chemistry / Q000187:drug effects; D011282:Pregnenediones / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011282:Pregnenediones; C023617:pregna-4,17-diene-3,16-dione; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase