The transcriptional factors HIF-1 and HIF-2 and their novel inhibitors in cancer therapy.

: Hypoxia is one of the intrinsic features of solid tumors, and it is always associated with aggressive phenotypes, including resistance to radiation and chemotherapy, metastasis, and poor patient prognosis. Hypoxia manifests these unfavorable effects through activation of a family of transcription factors, Hypoxia-inducible factors (HIFs) play a pivotal role in the adaptation of tumor cells to hypoxic and nutrient-deprived conditions by upregulating the transcription of several pro-oncogenic genes. Several advanced human cancers share HIFs activation as a final common pathway. : This review highlights the role and regulation of the HIF-1/2 in cancers and alludes on the biological complexity and redundancy of HIF-1/2 regulation. Moreover, this review summarizes recent insights into the therapeutic approaches targeting the HIF-1/2 pathway. : More studies are needed to unravel the extensive complexity of HIFs regulation and to develop more precise anticancer treatments. Inclusion of HIF-1/2 inhibitors to the current chemotherapy regimens has been proven advantageous in numerous reported preclinical studies. The combination therapy ideally should be personalized based on the type of mutations involved in the specific cancers, and it might be better to include two drugs that inhibit HIF-1/2 activity by synergistic molecular mechanisms.