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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112Bornmann -
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539Danishefsky -
319Chou -
17
Zatorska
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