Human
thioredoxin has been implicated in
cancer as a growth stimulator through regulation of DNA replication and
growth factor activity, as a modulator of
transcription factor activity, and as an inhibitor of apoptosis. In the present study, the steady-state level of
thioredoxin protein was examined in a number of
cancer cell lines. Interestingly,
thioredoxin expression is elevated in a variety of human tumor cell lines compared with normal cell lines. The altered expression of
thioredoxin in
tumor cells suggests it may be a target in the development of novel therapeutic agents for the treatment and prevention of
cancer. Further to this possibility, 26 phosphorothioate antisense
oligodeoxynucleotides (PS-AS-ODNs) were evaluated for the ability to inhibit
thioredoxin expression in cell culture. One PS-AS-ODN, GTI-2601, specifically reduced the levels of
thioredoxin mRNA and
protein, exhibited potent anti-proliferative effects on colony formation in vitro, and had anti-
tumor effects in human
tumor xenograft mouse models in vivo. Sequence-specific decreases in
thioredoxin expression levels were accompanied by significant suppression of
tumor growth in mice. Taken together, these data suggest that
thioredoxin may be a useful target for developing PS-AS-ODNs as drug candidates against human
cancer.