The use of Tris‐Lipidation to modify drug cytotoxicity in multidrug resistant cells expressing P‐glycoprotein or MRP1

Abstract

1 Increasing the lipophilicity is a strategy often used to improve a compound's cellular uptake and retention but this may also convert it into a substrate for an ATP-dependent transporter such as Pglycoprotein or the multidrug resistance-associated protein (MRP1), which are involved in cellular e ux of drugs. Tris-Lipidation of compounds is a convenient way of modifying drug lipophilicity and generating an array of derivatives with diverse properties. 2 To determine the e ect of Tris-Lipidation on a drug's cytoxicity in multidrug resistant cells, various glycyl-Tris-mono-(GTP1), di-(GTP2) and tri-palmitate (GTP3) derivatives were prepared of the cancer chemotherapeutic drugs chlorambucil and methotrexate, and of the anti-HIV drug AZT. The cytotoxicity of these derivatives and their parent compounds was determined in the CEM/ VLB 100 cells with increased P-glycoprotein expression, the CEM/E1000 cells that overexpress MRP1 and the parent, drug-sensitive CCRF-CEM cells. 3 Increasing the lipophilicity of AZT increased its cytotoxicity in the sensitive CCRF-CEM parental cell line while decreased cytotoxicity was observed for the methotrexate derivatives. For the chlorambucil derivatives, both increased (GTP1) and decreased (GTP2) cytotoxicity occurred in the CCRF-CEM cells. With the exception of AZT-GTP1, all GTP1 and GTP2 derivatives of chlorambucil, methotrexate and AZT had decreased cytotoxicity in the P-glycoprotein-expressing CEM/VLB 100 cells while chlorambucil-GTP1, methotrexate-GTP2 and methotrexate-GTP3 were the only compounds with decreased cytotoxicity in the MRP1-overexpressing CEM/E1000 cells. 4 The number of palmitate residues, the position of derivatisation and the type of linkage all may a ect the P-glycoprotein and MRP1 substrate properties. 5 Tris-Lipidation may therefore provide a useful way of manipulating the pharmacokinetic properties of drugs.

Nitrogen monoxide (NO)-mediated iron release from cells is linked to NO-induced glutathione efflux via multidrug resistance-associated protein 1

“…In contrast, there was no difference in NO-mediated 59 Fe release comparing CCRF-CEM VLB-100 cells that hyperexpress MDR1 (24) to WT CCRF-CEM cells (unpublished data).…”

Hydrophobic Transmembrane-Peptide Lipid Conjugations Enhance Membrane Binding and Functional Activity in T-Cells

“…Earlier work involving Tris conjugation (7-10, 12) has given interesting and important results concerning the design and potential therapeutic application of this system. In one study, one, two, or three palmitic acid groups were conjugated to three different drugs, chlorambucil, AZT, and methotrexate, whereupon the cytotoxicity of each compound was compared in various multidrug resistant cell lines (10). In general, Davey et al (10) noted a trend in which the cytoxicity of each conjugated compound decreased with increasing numbers of palmitic acid groups.…”

“…To determine the effect of Tris-lipidation on a drug's cytoxicity in multidrug resistant cells, Davey et al (10) also investigated the effect and cytotoxicity of various Gly-Tris-Palmitate (GTP1, GTP2, and GTP3) derivatives of the cancer chemotherapeutic drugs chlorambucil and methotrexate, and of the anti-HIV drug AZT in comparison to parent drugs.…”

The search for new amphiphiles: synthesis of a modular, high-throughput library

“…TRIS has been used previously for the synthesis of amphiphilic drug-delivery vehicles, with advantages including its inexpensive availability and non-toxic nature [34–35]. …”

“…For the triple-chained tails, triol 15 was synthesised from tris(hydroxymethyl)methylamine (TRIS) and 4-pentynoic acid using ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), following a similar method to Pucci et al ( Scheme 2 ) [ 33 ]. TRIS has been used previously for the synthesis of amphiphilic drug-delivery vehicles, with advantages including its inexpensive availability and non-toxic nature [ 34 – 35 ].…”