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Cancer Chemother Pharmacol. 2006 Jul;58(1):99-106. Epub 2005 Oct 18.

Dibenzocyclooctadiene lingnans: a class of novel inhibitors of P-glycoprotein.

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1
The Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, People's Republic of China.

Abstract

PURPOSE:

To determine if five dibenzocyclooctadiene lingnans, a class of naturally occurring compounds from Schisandra chinensis (Turcz.) Baill, have the activities to reverse P-glycoprotein (P-gp) mediated multidrug resistance (MDR).

METHODS:

The IC(50)s of four MDR cell lines (K562/Adr, MCF-7/Adr, KBv200, and Bcap37/Adr) toward daunorubicin, vincristine, and paclitaxel in the presence or absence of one of the dibenzocyclooctadiene lingnans were determined by a FACscan assay. The intracellular daunorubicin accumulation in the four MDR cell lines was determined by incubation of cells with daunorubicin (2 microg/ml) in the presence or absence of one of the dibenzocyclooctadiene lingnans by a FACscan assay. The interaction of the five dibenzocyclooctadiene lingnans with P-gp was assayed by their inhibition of (3)H-azidopine photoaffinity labeling of P-gp.

RESULTS:

Among the five lingnans, while schisandrin A and B, and schisantherin A demonstrated strong and comparable activities to reverse the drug resistance and the intracellular drug accumulation in four MDR cell lines, schisandrol A and B showed very limited activities. The poor activities of schisandrol A and B are possibly caused by the hydroxyl groups on the cyclooctadiene ring, because the activities of the molecules resumed when the hydroxyl group was esterified to form a benzoate. Further studies demonstrated that these compounds physically interacted with P-gp.

CONCLUSION:

Schisandrin A and B, and schisantherin A are potent P-gp inhibitor and is of potential for future clinical application.

PMID:
16231181
DOI:
10.1007/s00280-005-0133-1
[Indexed for MEDLINE]
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