Fig. 3

Inhibition of HIF-1α and HIF-2α in combination with chemotherapy, radiotherapy, and targeted therapy. Chemotherapy such as Cisplatin and 5-FU can cause DNA damage and cancer cell apoptosis. Radiotherapy can increase the level of ROS and lead to cancer cell apoptosis. However, during hypoxia, tumor cell HIF-1 pathway will be activated and result in therapy resistance. For chemotherapy resistance induced by HIF pathway, cancer cell can promote chemo-drug pump out, undergo DNA repairment, inhibit cell apoptosis and shift cell metabolism. And radiotherapy resistance is made by angiogenesis and more blood supply which promote cancer cell survival. Therefore, many synergistic effects by the combination therapy of HIF inhibitor and chemo, radio and targeted therapy through reversing the resistance by HIF pathway. The effects are seen in vivo and in vitro of varied cancer cell type. • Chemotherapy includes cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, irinotecan. • HIF-1 pathway inhibitor includes erlotinib (EGFR inhibitor); HS-173 (PI3K inhibitor); everolimus/sirolimus (m-TOR inhibitor); Panobinostat (HDAC inhibitor); EZN-2698, PX-478, 2ME2, Camptothecin (HIF-1α translation inhibitor); Acriflavine (HIF-1α dimerization inhibitor); Echinomycin and Anthracycline (HIF-1α DNA-binding inhibitor). • HIF-2 pathway inhibitor includes PT-2385 and PT-2977. • The impact of cancer therapy (White words with blue background). • The effect of activated HIF-1 pathway (White words with green background). If given HIF inhibitor, the downstream mechanism of HIF would decrease (Dotted lines). Abbreviations: PI3K = Phosphoinositide-3-kinase; Akt = protein kinase B; mTOR = mechanistic target of rapamycin VEGF = Vascular endothelial growth factor; VEGFR = Vascular endothelial growth factor receptor; EGF = Epidermal growth factor; IGF-1 = Insulin like growth factor-1; GLUT = Glucose transporter; BCL-2 = B-cell lymphoma 2; EPO = Erythropoietin; HIF = hypoxia inducible factor; HRE = Hypoxia-response element; HSP90 = Heat shock protein 90; ROS = Reactive oxygen species; TOP1 = Topoisomerase1