Natural compounds and the hypoxia-inducible factor (HIF) signalling pathway

A decline in the tissue oxygen level below normal leads to cellular hypoxia. This situation is very frequently encountered in solid tumors as existing blood vessels cannot satisfy the requirements in oxygen of the rapidly growing tumor. Like hyperoxia, hypoxia is a stress factor for cells and tissues. Adapting to this stressful situation leads to activation of the dimeric transcription factor hypoxia-inducible factor-1 (HIF-1) that induces gene expression in promoting tumor cell survival. In addition, hypoxia acts as a selection factor for radio- and chemotherapy resistant tumor cells with a high potential of malignancy. Consequently, over expression of the HIF-1alpha subunit is associated with an advanced disease stage and poor prognosis of cancer patients. During the last few years intense effort has been made in investigating natural compounds that can be used as HIF-1 inhibitors. These compounds aim to suppress tumor hypoxia and to increase the susceptibility of tumor cells to radio- and chemo-therapy. In this review we summarize recent findings concerning HIF-1 regulation and present a survey of HIF-1 inhibiting natural compounds that have been discovered in the last few years.