Hypoxia-inducible factor-1 (HIF-1) has been recognized as an important cancer drug target. Many recent studies have provided convincing evidences of strong correlation between elevated levels of HIF-1 and tumor metastasis, angiogenesis, poor patient prognosis as well as tumor resistance therapy. It was found that hypoxia (low O2 levels) is a common character in many types of solid tumors. As an adaptive response to hypoxic stress, hypoxic tumor cells activate several survival pathways to carry out their essential biological processes in different ways compared with normal cells. Recent advances in cancer biology at the cellular and molecular levels highlighted the HIF-1α pathway as a crucial survival pathway for which novel strategies of cancer therapy could be developed. However, targeting the HIF-1α pathway has been a challenging but promising progresses have been made in the past twenty years. This review summarizes the role and regulation of the HIF-1α in cancer, and recent therapeutic approaches targeting this important pathway.

Introduction: 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. Areas covered: 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. Expert opinion: 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.

We define previously unrecognized in vivo pathways of vitamin D ₃ (D3) metabolism generating novel D3‐hydroxyderivatives different from 25‐hydroxyvitamin D ₃ [25(OH)D3] and 1,25(OH) ₂ D3. Their novel products include 20‐hydroxyvitamin D ₃ [20(OH)D3], 22(OH)D3, 20,23(OH) ₂ D3, 20,22(OH) ₂ D3, 1,20(OH) ₂ D3,1,20,23(OH) ₃ D3, and 17,20,23(OH) ₃ D3 and were produced by placenta, adrenal glands, and epidermal keratinocytes. We detected the predominant metabolite [20(OH)D3] in human serum with a relative concentration ~20 times lower than 25(OH)D3. Use of inhibitors and studies performed with isolated mitochondria and purified enzymes demonstrated involvement of the steroidogenic enzyme cytochrome P450scc (CYP11A1) as well as CYP27B1 (1α‐hydroxylase). In placenta and adrenal glands with high CYP11A1 expression, the predominant pathway was D3 → 20(OH)D3 → 20,23(OH) ₂ D3 → 17,20,23(OH) ₃ D3 with further 1α‐hydroxylation, and minor pathways were D3 → 25(OH)D3 → 1,25(OH) ₂ D3 and D3 → 22(OH)D3 → 20,22(OH) ₂ D3. In epidermal keratinocytes, we observed higher proportions of 22(OH)D3 and 20,22(OH) ₂ D3. We also detected endogenous production of 20(OH)D3, 22(OH) D3, 20,23(OH) ₂ D3, 20,22(OH) ₂ D3, and 17,20,23(OH) ₃ D3 by immortalized human keratinocytes. Thus, we provide in vivo evidence for novel pathways of D3 metabolism initiated by CYP11A1, with the product profile showing organ/cell type specificity and being modified by CYP27B1 activity. These findings define the pathway intermediates as natural products/endogenous bioregulators and break the current dogma that vitamin D is solely activated through the sequence D3 → 25(OH)D3 → 1,25(OH) ₂ D3.—Slominski, A. T., Km, T.‐K., Shehabi, H. Z., Semak, I., Tang, E. K. Y., Nguyen, M. N., Benson, H. A. E., Korik, E., Janjetovic, Z., Chen, J., Yates, C. R., Postlethwaite, A. , Li, W., Tuckey, R. C. In vivo evidence for a novel pathway of vitamin D ₃ metabolism initiated by P450scc and modified by CYP27B1. FASEB J. 26, 3901–3915 (2012). www.fasebj.org