Abstract：
:The dithiol-reducing thioredoxin/thioredoxin reductase system normally maintains the reduced state of key enzymes responsible for the cell's anti-oxidant defences. We therefore addressed the question of whether AW 464--a novel thioredoxin inhibitor--as well as broad spectrum dithiol ligands diamide and phenylarsine oxide are able to induce and execute a regular apoptotic sequence of events without overwhelming the cell's ability to detoxify reactive oxygen species. All three agents were found to target the thioredoxin system in a cell-free assay. In HL-60 leukaemia cells, they were also found to induce Bak activation, cytochrome c release from mitochondria, decreasing Delta Psi m, chromatin condensation, phosphatidyl serine exposure and Tdt-sensitive DNA nicks. At the onset of apoptosis there was no evidence of increases in oxygen free radicals or peroxide in cells treated with AW 464 or diamide. Phenylarsine oxide induced both free radicals and hydrogen peroxide, but this did not appear to interfere with apoptosis. We conclude that pharmacological targeting of thioredoxin can induce a well-orchestrated apoptotic programme.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Pallis M,Bradshaw TD,Westwell AD,Grundy M,Stevens MF,Russell Ndoi
10.1016/s0006-2952(03)00471-4subject
Has Abstractpub_date
2003-11-01 00:00:00pages
1695-705issue
9eissn
0006-2952issn
1873-2968pii
S0006295203004714journal_volume
66pub_type
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