Asclepiasterol, a novel C21 steroidal glycoside derived from Asclepias curassavica, reverses tumor multidrug resistance by down-regulating P-glycoprotein expression
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Wei-Qi Yuan1,2,*, Rong-Rong Zhang1,*, Jun Wang1, Yan Ma2, Wen-Xue Li2, Ren-Wang Jiang1, Shao-Hui Cai1
1College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China
2Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, 511430, P. R. China
*These authors have contributed equally to this work
Wen-Xue Li, email: [email protected]
Ren-Wang Jiang, email: [email protected]
Shao-Hui Cai, email: [email protected]
Keywords: asclepiasterol, steroid, multidrug resistance (MDR), P-glycoprotein, phosphorylation of ERK1/2 (P-ERK)
Received: December 10, 2015 Accepted: April 02, 2016 Published: April 25, 2016
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.
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