Hypoxia-mediated drug resistance: Novel insights on the functional interaction of HIFs and cell death pathways

Resistance towards chemotherapy, either primary or acquired, represents a major obstacle in clinical oncology. Three basic categories underlie most cases of chemotherapy failure: Inadequate pharmacokinetic properties of the drug, tumor cell intrinsic factors such as the expression of drug efflux pumps and tumor cell extrinsic conditions present in the tumor microenvironment, characterized by such hostile conditions as hypoxia, acidosis, nutrient starvation and increased interstitial pressure. Tumor hypoxia has been known to negatively affect therapy outcome for decades. Hypoxia inhibits tumor cell proliferation and induces cell cycle arrest, ultimately conferring chemoresistance since anticancer drugs preferentially target rapidly proliferating cells. However, this knowledge has been largely neglected while screening for anti-proliferative substances in vitro, resulting in hypoxia-mediated failure of most newly identified substances in vivo. To achieve a tangible therapeutic benefit from this knowledge, the mechanisms that drive tumoral responses to hypoxia need to be identified and exploited for their validity as innovative therapy targets. The HIF family of hypoxia-inducible transcription factors represents the main mediator of the hypoxic response and is widely upregulated in human cancers. HIF-1α and to a lesser extent HIF-2α, the oxygen-regulated HIF isoforms, have been associated with chemotherapy failure and interference with HIF function holds great promise to improve future anticancer therapy. In this review we summarize recent findings on the molecular mechanisms that underlie the role of the HIFs in drug resistance. Specifically, we will highlight the multifaceted interaction of HIF with apoptosis, senescence, autophagy, p53 and mitochondrial activity and outline how these are at the heart of HIF-mediated therapy failure.