Reversal of Anticancer Multidrug Resistance by the Ardeemins

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...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 95; no. 14; pp. 8369 - 8374
Main Authors:	Chou, Ting-Chao, Depew, Kristopher M., Zheng, Yu-Huang, Safer, Michelle L., Chan, Daniel, Helfrich, Barbara, Zatorska, Danuta, Zatorski, Andrzej, Bornmann, William, Danishefsky, Samuel J.
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences of the United States of America 07-07-1998 National Acad Sciences National Academy of Sciences The National Academy of Sciences
Subjects:	Alkaloids - pharmacology Alkaloids - therapeutic use Animals Antibiotics, Antineoplastic - pharmacology Antibiotics, Antineoplastic - therapeutic use Antineoplastic Agents, Phytogenic - pharmacology Antineoplastic Agents, Phytogenic - therapeutic use Biochemistry Biological Sciences Cancer Cell growth Cell lines Chemotherapy Cytotoxicity Dosage Doxorubicin - pharmacology Doxorubicin - therapeutic use Drug resistance Drug Resistance, Multiple - genetics Gene Expression Regulation, Neoplastic - drug effects Humans Indoles - pharmacology Indoles - therapeutic use Inhibitory concentration 50 Leukemia Leukemia, Experimental - drug therapy Leukemia, Experimental - genetics Leukemia, Lymphoid - drug therapy Leukemia, Lymphoid - genetics Lungs Medical treatment Mice Pharmacology Pyrimidinones - pharmacology Pyrimidinones - therapeutic use Synergism Tumor Cells, Cultured Tumors Vinblastine - pharmacology Vinblastine - therapeutic use
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Summary:	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 μ M 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 B6D2F1mice 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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 To whom reprint requests should be addressed. e-mail: dshfsky@ski.mskcc.org. Contributed by Samuel J. Danishefsky
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.95.14.8369