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: Wei-Qi Yuan, Rong-Rong Zhang, Jun Wang, Yan Ma, Wen-Xue Li, Ren-Wang Jiang, Shao-Hui Cai
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 21 Pg. 31466-83 (May 24 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27129170 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Glycosides
• Phytosterols
• Saponins
• asclepiasterol
• Extracellular Signal-Regulated MAP Kinases

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (genetics, metabolism)
• Apoptosis (drug effects)
• Asclepias (chemistry)
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Drug Resistance, Multiple (drug effects, genetics)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glycosides (chemistry, pharmacology)
• Hep G2 Cells
• Humans
• MCF-7 Cells
• Molecular Structure
• Phosphorylation (drug effects)
• Phytosterols (chemistry, pharmacology)
• Saponins (chemistry, pharmacology)