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Isolation of P-glycoprotein inhibitors from Schisandra chinensis extract.

Date:2016/9/26 23:58:19

Isolation of P-glycoprotein inhibitors from Schisandra chinensis extract.

Schisandra chinensis (Schisandraceae) is a well-known medicinal plant in traditional Chinese medicine. 

Recently was found that dibenzocyclooctadiene lignans inhibit ATP binding cassette (ABC) transporters, 

P-glycoprotein and multidrug resistance-associated protein 1 (MRP1), which export drugs out of the cancer 

cells. In our previous study, we have isolated nine dibenzo[a,c]cyclooctadiene lignans, schizandrin, gomisin A, 

gomisin N, gomisin J, angeloylgomisin H, tigloylgomisin P, deoxyschizandrin, gamma-schizandrin and wuweizisu C 

from seeds of Schisandra chinensis and lignans were examined for their effect on doxorubicin-resistant human 

lung carcinoma COR-L23/R cell line over-expressing MRP1. We have found that two lignans, R-(+)-deoxyschizandrin 

and R,S-gamma-schizandrin at relatively non-toxic concentrations enhanced the accumulation of doxorubicin in 

COR-L23/R cells and restored the cytotoxic action of doxorubicin on drug-resistant cells (Slaninov et al.: 

Toxicology in Vitro 23, 2009, 1047). In order to obtain more effective lignans, the methanolic extracts of 

Schisandra chinensis extract seed and stem were screened for their effect on accumulation of doxorubicin 

in promyelotic leukaemia cells HL60/MDR overexpressing P-glycoprotein. The methanolic extract of both seed 

and stem increased intracellular doxorubicin accumulation. Activity-guided fractionation of both methanolic 

extracts on SPE cartridges Supelco LC 18 showed that active compounds were present in the fraction rich in 

lignans. The lignan fraction originated from the seeds was further purified by semi-preparative HPLC on a C18 

column to give three subfraction with higher ability of doxorubicin accumulation than that of deoxyschizandrin.

 Further separation of one of these fractions on a semi-preparative C18 column provided two new lignans, which 

accumulated doxorubicin inside the HL60/MDR cells more effectively than well-known P-glycoprotein inhibitor 

verapamil or deoxyschizandrin.