Multidrug resistance reversal properties and cytotoxic evaluation of representatives of a novel class of HIV-1 protease inhibitors

J Pharm Pharmacol. 2010 Dec;62(12):1704-10. doi: 10.1111/j.2042-7158.2010.01144.x. Epub 2010 Oct 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Survival / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple / drug effects*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / pharmacology*
  • Hep G2 Cells
  • Humans
  • Jurkat Cells
  • Lymphoma, T-Cell
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Ritonavir / pharmacology*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • HIV Protease Inhibitors
  • Ritonavir