Reversal of P-glycoprotein-mediated multidrug resistance by Alisol B 23-acetate.
Herbal drugs were screened for their activity in reversing multidrug resistance (MDR) in P-glycoprotein (P-gp) over-expressing cancer cells. Through bio-assay guided fractionation an active compound was isolated from Rhizoma Alismatis, the underground part of Alisma orientale and the chemical structure of the isolate compound was confirmed by HPLC, LC-MS and NMR as Alisol B 23-acetate (ABA). ABA restored the sensitivity of MDR cell lines HepG2-DR and K562-DR to anti-tumor agents that have different modes of action but are all P-gp substrates. It restored the activity of vinblastine, a P-gp substrate, in causing G2/M arrest in MDR cells. In a dose-dependent manner, ABA increased doxorubicin accumulation and slowed down the efflux of rhodamin-123 from MDR cells. ABA inhibited the photoaffinity labeling of P-gp by [125I]iodoarylazidoprazosin and stimulated the ATPase activity of P-gp in a concentration-dependent manner, suggesting that it could be a transporter substrate for P-gp. In addition, ABA was also a partial non-competitive inhibitor of P-gp when verapamil was used as a substrate. Our results suggest that ABA may be a potential MDR reversal agent and could serve as a lead compound in the development of novel drugs.
Department of Biology and Chemistry, Bioactive Products Research Group, City University of Hong Kong, Kowloon, Hong Kong SAR, China.
Cheng
C
Wang
Jin-Xia
JX
Zhang
Xiao-Ling
XL
Shen
Chi-Keung
CK
Wan
Anfernee Kai-Wing
AK
Tse
Wang-Fun
WF
Fong
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D002783:Cholestenones / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007457:Iodine Radioisotopes; D020014:K562 Cells; D019920:Photoaffinity Labels / Q000378:metabolism; D012238:Rhodium / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002783:Cholestenones; D007457:Iodine Radioisotopes; D019920:Photoaffinity Labels; C457232:alisol B; D014747:Vinblastine; D004317:Doxorubicin; D012238:Rhodium; D000251:Adenosine Triphosphatases