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Hypoxia develops in the majority of solid tumors due to the inability of the existing vascular system to supply the growing tumor mass with adequate amounts of oxygen. A large body of clinical evidence suggests that intratumoral hypoxia correlates with the elevated aggressive behavior of cancer cells and their resistance to therapy, leading to poor patient prognoses. A heterodimeric transcription factor, hypoxia inducible factor-1 (HIF-1), has been shown to orchestrate a large number of molecular events required for the adaptation of tumor cells to hypoxia. Therefore, HIF-1 has become an attractive target for the development of anti-cancer drugs. Here, we highlight some of the recently developed small-molecule inhibitors of HIF-1 function. These drugs disrupt the HIF-1 signaling pathway through a variety of mechanisms, including the inhibition of HIF-1α protein synthesis, stabilization, nuclear translocation and HIF-1 transactivation of target genes.