HIF-1 (Hypoxia Inducible Factor-1) Signalling

Hypoxia (low concentrations of oxygen) is a common feature of many human cancers, including head and neck, cervix, breast, and lung. Hypoxic cells stimulate cellular responses such as inhibition of apoptosis, promotion of angiogenesis and metastasis. All of these responses are mediated through the protein HIF-1 (hypoxia-inducible factor-1).

Hypoxic tumour cells are resistant to radiotherapy and to many commonly used anti-cancer drugs, and can cause patients to relapse after initial cancer treatment.

Because of its role in regulating the response of growing tumours to hypoxia, HIF-1 represents an important target for new anti-cancer drugs.

In in vitro experiments, PMX 464 and PMX 290 are potent inhibitors of HIF-1 mediated signal transduction. Both compounds inhibit the expression of proteins which promote cell survival under hypoxic conditions.

PMX 464 and PMX 290 cause dose-dependent down regulation of HIF-mediated gene transactivation. Carbonic anhydrase IX and BNIP3 protein expression, induced under hypoxia, are powerfully inhibited following treatment of cells with both compounds.

	Novel thioredoxin inhibitors paradoxically increase Hypoxia-inducible factor-Î± expression but decrease functional transcriptional activity, DNA binding, and degradation.

	Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study.

	Elucidation of thioredoxin as a molecular target for antitumour quinols.

	Induction and apoptosis without redox catastrophe by thioredoxin-inhibitory compounds.