Anti-proliferative and anti-tumor effects of antisense oligonucleotide GTI-2601 targeted against human thioredoxin

Abstract

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.