Characterization of prenylcysteines that interact with P-glycoprotein and inhibit drug transport in tumor cells.

Abstract

Prenylcysteine methyl esters that represent the C-terminal structures of prenylated proteins demonstrate specific substrate-like interactions with P-glycoprotein (Zhang, L., Sachs, C. W., Fine, R. L., and Casey, P. J. (1994) J. Biol. Chem. 269, 15973-15976). The simplicity of these compounds provides a unique system for probing the structural specificity of P-glycoprotein substrates. We have further assessed the structural elements of prenylcysteines involved in the interaction with P-glycoprotein. Carboxyl group methylation, a modification in many prenylated proteins, plays an essential role of blocking the negative charge at the free carboxylate. Substitution of the methyl ester with a methyl amide or simple amide does not change the ability of the molecule to stimulate P-glycoprotein ATPase activity, but substitution with a glycine is not tolerated unless the carboxyl group of glycine is methylated. The presence of a nitrogen atom, which is found in many P-glycoprotein substrates and modifiers, is also essential for prenylcysteines to interact with P-glycoprotein. The structure at the nitrogen atom can, however, influence the type of interaction. Acetylation of the free amino group of prenylcysteine/results in a significant loss in the ability of prenylcysteines to stimulate P-glycoprotein ATPase activity. Instead, certain acetylated prenylcysteines behave as inhibitors of this activity. In studies using MDR1-transfected human breast cancer cells, the acetylated prenylcysteine analogs inhibit P-glycoprotein-mediated drug transport and enhance the steady-state accumulation of [3H]vinblastine, [3H]colchicine, and [3H]taxol. These inhibitors do not, however, affect drug accumulation in parental cells. These studies provide a novel approach for designing P-glycoprotein inhibitors that could prove effective in reversing the phenotype of multidrug resistance in tumor cells.

• Authors: L Zhang, C W Sachs, H W Fu, R L Fine, P J Casey
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 270 Issue 39 Pg. 22859-65 (Sep 29 1995) ISSN: 0021-9258 [Print] United States
• PMID: 7559420 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Recombinant Proteins
• Adenosine Triphosphatases
• Cysteine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (biosynthesis, metabolism)
• Adenosine Triphosphatases (metabolism)
• Animals
• Biological Transport (drug effects)
• Breast Neoplasms
• Cell Line
• Cell Membrane (metabolism)
• Cysteine (analogs & derivatives, pharmacology)
• Drug Resistance, Multiple (genetics)
• Female
• Humans
• Kinetics
• Recombinant Proteins (biosynthesis, metabolism)
• Spodoptera
• Structure-Activity Relationship
• Transfection
• Tumor Cells, Cultured