Inhibition of drug-naive and -resistant leukemia cell proliferation by low molecular weight thiols

Abstract

The aim of these studies was to investigate the ability of cysteamine and its congeners to arrest the proliferation of leukemic cells and to determine the physico-chemical properties responsible for this ability. Fifteen low molecular weight thiol-bearing compounds were shown to arrest the proliferation of CCRF-CEM cells and a methotrexate-resistant subline, with IC50 values between 10(-5) and 10(-4) M. Cysteamine arrested proliferation by slowing the passage of cells through S phase. These cells subsequently resumed cycling, although a proportion went on to die by apoptosis. The antiproliferative action of cysteamine was shown to depend, in part, on H2O2 production. This ability to generate peroxide is shared by many thiol compounds, and molecular modeling indicated that thiol groups were required for the antiproliferative actions of the congeners of cysteamine. Molecular modeling also revealed that the most efficacious antiproliferative agents were those that had their amino acid and thiol moieties separated by an intramolecular distance of 3.17 to 5.9 A, as exemplified by WR 1065 and the aminothiophenols. These findings indicate that thiol-bearing compounds may have some efficacy in the treatment of drug-naive and -resistant leukemia cells.