title: 20S-protopanaxadiol inhibits P-glycoprotein in multidrug resistant cancer cells.
abstract: One of the major causes for cancer cells to resist current chemotherapy is attributed to the over-expression of P-glycoprotein (P-gp), resulting in insufficient drug delivery to the tumor sites. Protopanaxadiol ginsenosides Rg3 and Rh2 are known to induce apoptosis and significantly enhance the tumor inhibitory effects of chemotherapeutics in a synergistic fashion. One of the possible mechanisms is by blocking P-gp activity. The final deglycosylation metabolite of protopanaxadiols (PPDs) IN VIVO is 20S-protopapanaxadiol (aglycone PPD, aPPD), which has also shown anticancer activity and synergy with chemotherapy drugs. In the present study, P-gp over-expressing cancer cells were utilized to test whether aPPD also inhibits P-gp activity. We found that aPPD caused similar cytotoxicity in P388adr cells as their parental non-MDR cells, suggesting that aPPD may not be a substrate of P-gp. On the other hand, the calcein AM efflux assay showed that aPPD was able to inhibit P-gp activity as potently as verapamil on MDR cells. The blockage of P-gp activity was highly reversible as wash-out of aPPD resulted in an immediate recovery of P-gp activity. Unlike verapamil, aPPD did not affect ATPase activity of P-gp suggesting a different mechanism of action. The above results indicate that aPPD, unlike its precursor ginsenosides Rg3 and Rh2, is not a substrate of P-gp. It is also the first time that aPPD has showed a reversible nature of its P-gp inhibition. In addition to its pro-apoptotic nature, aPPD may be a potential new P-gp inhibitor for cancer treatment.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Luke
authors.initials: L
authors.lastname: Bu
authors.forename: Hang
authors.initials: H
authors.lastname: Yan
authors.forename: William
authors.initials: W
authors.lastname: Jia
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D051379:Mice; D012502:Sapogenins / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012502:Sapogenins; D000251:Adenosine Triphosphatases; C062916:protopanaxadiol