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


CONCLUSIONS
Schisandrin A and B, and schisantherin A are potent P-gp inhibitor and is of potential for future clinical application.
Pan
Qiangrong
Q
The Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, People's Republic of China.
Lu
Qinghua
Q
Zhang
Kun
K
Hu
Xun
X
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D034242:Cyclooctanes / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D004149:Dioxoles / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D017705:Lignans / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000494:pharmacology*; D000091402:Prohibitins; D014750:Vincristine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D034242:Cyclooctanes; D004149:Dioxoles; D017705:Lignans; C000717331:PHB2 protein, human; D011083:Polycyclic Compounds; D000091402:Prohibitins; C015499:schizandrin B; D014750:Vincristine; C034734:schizandrin A; C034557:schizandrer A; D017239:Paclitaxel; D003630:Daunorubicin