Targeting of Hypoxia for Therapeutic Strategy in the Varied Physiological States

Abstract

Hypoxia-inducible factors (HIFs) are transcription factors that initiate the expression of cellular processes to cope with hypoxic conditions. HIFs are principal regulators of hypoxic adaptation, regulating gene expression involved in glycolysis, erythropoiesis, angiogenesis, proliferation, and stem cell function under low O2. HIFs may play a pivotal role in tumor survival and metastasis in cancer formation and growth. Likewise, HIFs play a key role in microbial pathogenesis, particularly in host-pathogen interaction. Because of the role that HIF-1alpha plays in the biology of cancer and infections, it is a potential therapeutic target not only for malignant growth but also for parasitic infection. Several reports have demonstrated the up-regulation of host cellular HIFs due to infection-induced hypoxia. Hypoxia-inducible pathways have attracted great interest in the down-regulation of prolyl hydroxylase for treating inflammatory diseases and infections by viruses, protozoa, or bacteria, among other pathogens. Interestingly, increasing evidence suggests that HIFs play an important regulatory role in inflammation. For example, in macrophages, HIFs regulate glycolytic energy generation and optimize innate immunity, control pro-inflammatory gene expression, mediate the killing of pathogens and influence cell migration. Therefore, a good understanding of the biochemical mechanism of hypoxia signaling pathways will shed more light on how it could help identify and develop new treatment strategies for cancer and parasitic diseases, including viral, bacterial, fungal and protozoa infections.