Open AccessReversal of anticancer multidrug resistance by the ardeemins
Author(s) -
TingChao Chou,
Kristopher M. Depew,
Yu-Huang Zheng,
Michelle L. Safer,
Daniel C. Chan,
Barbara A. Helfrich,
Danuta Zatorska,
Andrzej Zatorski,
William G. Bornmann,
Samuel J. Danishefsky
Publication year - 1998
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.95.14.8369
Subject(s) - multiple drug resistance , p glycoprotein , in vivo , efflux , in vitro , pharmacology , doxorubicin , biology , vinblastine , abcg2 , cell culture , drug resistance , chemotherapy , biochemistry , atp binding cassette transporter , microbiology and biotechnology , transporter , genetics , gene
Two “reverse prenyl” hexahydropyrroloindole alkaloids, 5-N -acetylardeemin and 5-N -acetyl-8-demethylardeemin, were evaluated as reversal agents in cells exhibiting a multidrug resistant (MDR) phenotype. These ardeemins (i ) reversed drug resistance to vinblastine (VBL) or to taxol as much as 700-fold at relatively noncytotoxic concentrationsin vitro ; (ii ) as a single agent at high concentrations killed MDR cells more efficaciously than the respective parent wild-type cells; and (iii ) exhibited strong synergistic effects with doxorubicin (DX) and VBL against the growth of MDR neoplastic cells, and to a lesser extent, of the parent wild-type cells. Mechanistic studies showed that photoaffinity labeling of P-glycoprotein (Pgp) with [3 H] azidopine was competitively inhibited by the ardeemins. Resistance to DX in MDR-[Pgp+ and MDR-associated protein (MRP)+ ], MDR-Pgp+ , lung resistance protein (LRP)+ -expressing, and wild-type lung cancer cells were reversed 110- to 200-fold, 50- to 66-fold, 7- to 15-fold, and 0.9- to 3-fold, respectively, by 20 μM of the ardeemins. Moreover, these compounds increased the intracellular accumulation of VBL and markedly decreased its efflux. Finally,in vivo combination studies demonstrated that nontoxic doses of the ardeemins with DX significantly improved the chemotherapeutic effects in B6D2F1 mice bearing DX-resistant P388 leukemia, and nude mice bearing human MX-1 mammary carcinoma xenografts. The above features indicate that the ardeemins may have utility in the therapy of cancer.