Reversal of anticancer multidrug resistance by the ardeemins Journal Article


Authors: Chou, T. C.; Depew, K. M.; Zheng, Y. U. H.; Safer, M. L.; Chan, D.; Helfrich, B.; Zatorska, D.; Zatorski, A.; Bornmann, W.; Danishefsky, S. J.
Article Title: Reversal of anticancer multidrug resistance by the ardeemins
Abstract: 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 concentrations in 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 [3H] 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.
Keywords: controlled study; unclassified drug; human cell; doxorubicin; nonhuman; paclitaxel; mouse; phenotype; animals; mice; animal experiment; animal model; antineoplastic agents, phytogenic; antineoplastic activity; cytotoxicity; drug resistance; tumor cells, cultured; pyrimidinones; vinblastine; gene expression regulation, neoplastic; nude mouse; indoles; antibiotics, antineoplastic; alkaloids; drug sensitivity; multidrug resistance; drug resistance, multiple; photoaffinity labeling; glycoprotein p; leukemia, lymphocytic; azidopine; humans; human; male; priority journal; article; leukemia, experimental; 5 n acetyl 8 demethylardeemin; 5 n acetylardeemin derivative; hexahydropyrroloindole; indole alkaloid
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 95
Issue: 14
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 1998-07-07
Start Page: 8369
End Page: 8374
Language: English
DOI: 10.1073/pnas.95.14.8369
PUBMED: 9653193
PROVIDER: scopus
PMCID: PMC20982
DOI/URL:
Notes: Article -- Export Date: 12 December 2016 -- Source: Scopus
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  1. William Bornmann
    112 Bornmann
  2. Ting-Chao Chou
    319 Chou