HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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 microM 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.
AuthorsT C Chou, K M Depew, Y H Zheng, M L Safer, D Chan, B Helfrich, D Zatorska, A Zatorski, W Bornmann, S J Danishefsky
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 95 Issue 14 Pg. 8369-74 (Jul 07 1998) ISSN: 0027-8424 [Print] United States
PMID9653193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • 5-N-acetyl-8-demethylardeemin
  • Alkaloids
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • Indoles
  • Pyrimidinones
  • 5-N-acetylardeemin
  • Vinblastine
  • Doxorubicin
Topics
  • Alkaloids (pharmacology, therapeutic use)
  • Animals
  • Antibiotics, Antineoplastic (pharmacology, therapeutic use)
  • Antineoplastic Agents, Phytogenic (pharmacology, therapeutic use)
  • Doxorubicin (pharmacology, therapeutic use)
  • Drug Resistance, Multiple (genetics)
  • Gene Expression Regulation, Neoplastic (drug effects)
  • Humans
  • Indoles (pharmacology, therapeutic use)
  • Leukemia, Experimental (drug therapy, genetics)
  • Leukemia, Lymphoid (drug therapy, genetics)
  • Mice
  • Pyrimidinones (pharmacology, therapeutic use)
  • Tumor Cells, Cultured
  • Vinblastine (pharmacology, therapeutic use)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: