Document Detail

Multidrug resistance reversal properties and cytotoxic evaluation of representatives of a novel class of HIV-1 protease inhibitors.
MedLine Citation:
PMID:  21054396     Owner:  NLM     Status:  MEDLINE    
OBJECTIVES: P-Glycoprotein (P-gp) plays a central role in the development of resistance against cytostatics in anticancer therapy and against human immunodeficiency virus (HIV) therapeutics of the HIV-1 protease inhibitor type. An approach to reverse the so-called multidrug resistance (MDR) phenomenon by the use of P-gp inhibiting agents is a challenge in the therapy of cancer and AIDS. Effective in-vitro inhibitors have P-gp substrate properties so that the expected in-vivo effects have been disappointing so far. Consequent higher dosages cause toxic effects.
METHODS: Novel HIV-1 protease inhibitors (H17, JW41, JW33 and JW46) have been evaluated in comparison with ritonavir as P-gp inhibiting agents, in the exclusively P-gp overexpressing model cell line mouse T lymphoma using flow cytometry. The cytotoxic properties against various cell lines were characterized in the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay to estimate potential toxic effects in therapeutically relevant concentrations in metabolically active HepG2 cells, drug-sensitive Jurkat cells and in gastric carcinoma cells.
KEY FINDINGS: Concentration-dependent effective reversal properties have been discussed in context and proved to be mainly influenced by the number of potential hydrogen bond acceptor functions. The compounds showed no cytotoxic properties in P-gp inhibiting concentration ranges. Ritonavir, a known P-gp substrate, proved to be less toxic in the P-gp expressing cell line than in the nonexpressing cell line at the cell-exposed concentrations and thus showed P-gp substrate properties. Two compounds, H17 and JW41, showed no P-gp substrate properties, with higher toxicity in the P-gp expressing cell line compared with the nonexpressing cell line.
CONCLUSIONS: The novel compounds have been shown to be prospective AIDS therapeutics, acting as effective and nontoxic P-gp inhibitors compared with ritonavir, which is a known P-gp inhibitor with unfavourable toxic and P-gp substrate properties.
Claudius Coburger; Hermann Lage; Joséf Molnár; Andreas Langner; Andreas Hilgeroth
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-04
Journal Detail:
Title:  The Journal of pharmacy and pharmacology     Volume:  62     ISSN:  2042-7158     ISO Abbreviation:  J. Pharm. Pharmacol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-11-08     Completed Date:  2011-05-11     Revised Date:  2011-09-13    
Medline Journal Info:
Nlm Unique ID:  0376363     Medline TA:  J Pharm Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1704-10     Citation Subset:  IM    
Copyright Information:
© 2010 The Authors. JPP © 2010 Royal Pharmaceutical Society of Great Britain.
Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany.
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MeSH Terms
Cell Line, Tumor
Cell Survival / drug effects*
Dose-Response Relationship, Drug
Drug Resistance, Multiple / drug effects*
HIV Protease Inhibitors / chemical synthesis,  pharmacology*
Hep G2 Cells
Jurkat Cells
Lymphoma, T-Cell
Mitochondria / drug effects,  metabolism
P-Glycoprotein / antagonists & inhibitors*,  metabolism
Ritonavir / pharmacology*
Reg. No./Substance:
0/HIV Protease Inhibitors; 0/P-Glycoprotein; 0/Ritonavir

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