title: Asclepiasterol, a novel C21 steroidal glycoside derived from Asclepias curassavica, reverses tumor multidrug resistance by down-regulating P-glycoprotein expression.
abstract: Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) is a major cause of cancer therapy failure. In this study, we identified a novel C21 steroidal glycoside, asclepiasterol, capable of reversing P-gp-mediated MDR. Asclepiasterol (2.5 and 5.0μM) enhanced the cytotoxity of P-gp substrate anticancer drugs in MCF-7/ADR and HepG-2/ADM cells. MDR cells were more responsive to paclitaxel in the presence of asclepiasterol, and colony formation of MDR cells was only reduced upon treatment with a combination of asclepiasterol and doxorubicin. Consistent with these findings, asclepiasterol treatment increased the intracellular accumulation of doxorubicin and rhodamine 123 (Rh123) in MDR cells. Asclepiasterol decreased expression of P-gp protein without stimulating or suppressing MDR1 mRNA levels. Asclepiasterol-mediated P-gp suppression caused inhibition of ERK1/2 phosphorylation in two MDR cell types, and EGF, an activator of the MAPK/ERK pathway, reversed the P-gp down-regulation, implicating the MAPK/ERK pathway in asclepiasterol-mediated P-gp down-regulation. These results suggest that asclepiasterol could be developed as a modulator for reversing P-gp-mediated MDR in P-gp-overexpressing cancer variants.
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.|Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 511430, P. R. China.
authors.forename: Wei-Qi
authors.initials: WQ
authors.lastname: Yuan
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 511430, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 511430, P. R. China.
authors.forename: Wen-Xue
authors.initials: WX
authors.lastname: Li
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
authors.forename: Ren-Wang
authors.initials: RW
authors.lastname: Jiang
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
authors.forename: Shao-Hui
authors.initials: SH
authors.lastname: Cai
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D031108:Asclepias / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006027:Glycosides / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D010840:Phytosterols / Q000737:chemistry / Q000494:pharmacology*; D012503:Saponins / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006027:Glycosides; D010840:Phytosterols; D012503:Saponins; C000625631:asclepiasterol; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: P-glycoprotein; asclepiasterol; multidrug resistance (MDR); phosphorylation of ERK1/2 (P-ERK); steroid