Downstream hypoxia inducible factor-1 (HIF-1) pathway Recently, microtubule-targeting agents (MTAs) have been found to share the property of downregulating HIF-1α, an instrumental factor in the oxygen-regulated angiogenesis and tumor growth. Importantly, inhibition of HIF-1 is downstream of microtubule disruption and is primarily believed to be through inhibition of the translation of HIF-1α (147). Low oxygen tension, or hypoxia, is a critical characteristic of approximately 50- 60% of advanced solid tumors. Hypoxia is a result of increased energy demand and diminished and abnormal vascular supply. Intratumoral hypoxia results when cells are located too far from functional blood supply for the diffusion of an adequate amount of oxygen. The presence of hypoxic regions of tumors was first postulated based on observations of the necrotic areas of tumors away from blood vessels (148). These hypoxic regions also result in a shift from oxidative metabolism to glycolysis, increased mutation rates, and upregulation of transcription for genes to deal with this anaerobic environment (149). Induction of HIF-1 represents the major response to reduced oxygen levels within a cell. HIF-1 is the name given to the heterodimeric complex comprised of the HIF-1α and HIF-1β subunits. HIF-1α is highly regulated in both an oxygen-dependent and oxygen-independent manner and was originally discovered as a protein that binds DNA at high-affinity when the hypoxia-mediated induction of the EPO gene was being investigated in 1995 (150). This discovery gave way to a molecular target for the presence of hypoxic regions in solid tumors. Since then, HIF-1 has been found to act as a transcription factor in many cell types (151). HIF-1 acts by localizing to the cis-acting hypoxia-responsive element and stimulating the transcription of more than 40 genes in response to hypoxia (152, 153). Many of these HIF-1 regulated genes result in an increase in glucose metabolism and angiogenesis, necessary for cellular survival in low oxygen tension. A deficiency in this complex results in developmental arrest, which is manifested as neural tube defects and cardiovascular malformations, and embryonic lethality (154, 155). HIF-1 also controls the transcription of survival factors and invasion factors, and overexpression of HIF-1 can lead to tumorgenesis. Additionally, upregulation of HIF-1 is correlated with a resistance to chemotherapy. Since the identification of the role of HIF-1 in cancer development, therapeutic strat...
