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Inhibition of HIFs as an Anti-Cancer Strategy

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 48025

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Prof. Dr. George Simos

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Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, 41500 Larissa, Greece
Interests: hypoxia; HIF-1; metabolism; phosphorylation; nuclear transport; cancer; apoptosis
Special Issues, Collections and Topics in MDPI journals

Dr. Ilias Mylonis

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Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, 41500 Larissa, Greece
Interests: Hypoxia; Hypoxia-inducible factor-1 (HIF-1); regulation of gene expression; cell signaling and cancer; nucleocytoplasmic transport; nuclear structure and function; regulation of lipid metabolism
Special Issues, Collections and Topics in MDPI journals

Dr. Georgia Chachami

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Laboratory of Biochemistry, Faculty of Medicine, University of Thessaly, Panepistimiou 3, BIOPOLIS, Larissa 41500, Greece
Interests: Hypoxia; Cancer cell metabolism & signaling; Hypoxia-Inducible Factors (HIFs); Regulation of transcription; Phosphorylation; Nucleocytoplasmic transport; Sumoylation; Transcription Factor AP-2alpha

Special Issue Information

Dear Colleagues,

Reduced oxygen availability (hypoxia) is a hallmark of the solid tumour microenvironment, a consequence of the elevated oxygen consumption by the rapidly proliferating cells and the inadequate vascularization of the tumour. Exposure of cells to hypoxic conditions results in dramatic changes in gene expression, coordinated by the hypoxia inducible transcription factors HIF-1 and HIF-2. HIFs regulate the expression of many genes that facilitate the adaptation of cancer cells to hypoxia including metabolic reprogramming, induction of angiogenesis, resistance to apoptosis or cytotoxic treatment, invasion and metastasis.

HIFs are heterodimeric transcriptional regulators comprised of one oxygen-regulated HIF-α subunit and one stably expressed HIF-β subunit or ARNT. The regulatory HIF-α subunits are frequently over-expressed in cancer cells not only due to local hypoxia but also because of oncogenic mutations (such as in VHL) or over-activation of signalling pathways such as PI3K-AKT-mTOR or Ras-ERK1/2 that stimulate HIF-α expression and/or HIF activity. Furthermore, HIF-α over-expression observed in many types of cancer is highly correlated with poor prognosis and patient mortality. HIFs have, therefore, become attractive targets for anticancer treatment. Pre-clinical as well as recent early clinical studies have shown that HIF inhibition can have therapeutic utility, especially in combination with traditional chemical or radiation treatments, which alone often fail to target the poorly oxygenated cancer cells in the tumour interior.

Although numerous HIF inhibitors have been reported, their useful application is limited by their lack of specificity and the poor characterisation of their molecular targets. Validation of known inhibitors and development of novel ones requires thorough understanding of the molecular/structural details, tissue/isoform specificity and oxygen-dependency of the mechanisms that fine-tune HIF activity in different types of cancer, which is still a matter of intense investigation. In-depth elucidation of the mechanisms that govern oncogenic HIF activation can allow their effective targeting and may offer remarkable possibilities to restrict tumour growth and essentially treat cancer.

Prof. Dr. George Simos
Dr. Ilias Mylonis
Dr. Georgia Chachami
Guest Editors

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Research

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18 pages, 11302 KiB

Open AccessArticle

Therapeutic Effects of Inhibition of Sphingosine-1-Phosphate Signaling in HIF-2α Inhibitor-Resistant Clear Cell Renal Cell Carcinoma

by Rouven Hoefflin, Sabine Harlander, Behnaz A. Abhari, Asin Peighambari, Mojca Adlesic, Philipp Seidel, Kyra Zodel, Stefan Haug, Burulca Göcmen, Yong Li, Bernd Lahrmann, Niels Grabe, Danijela Heide, Melanie Boerries, Anna Köttgen, Mathias Heikenwalder and Ian J. Frew

Cancers 2021, 13(19), 4801; https://doi.org/10.3390/cancers13194801 - 25 Sep 2021

Cited by 6 | Viewed by 3202

Abstract

Specific inhibitors of HIF-2α have recently been approved for the treatment of ccRCC in VHL disease patients and have shown encouraging results in clinical trials for metastatic sporadic ccRCC. However, not all patients respond to therapy and pre-clinical and clinical studies indicate that intrinsic as well as acquired resistance mechanisms to HIF-2α inhibitors are likely to represent upcoming clinical challenges. It would be desirable to have additional therapeutic options for the treatment of HIF-2α inhibitor resistant ccRCCs. Here we investigated the effects on tumor growth and on the tumor microenvironment of three different direct and indirect HIF-α inhibitors, namely the HIF-2α-specific inhibitor PT2399, the dual HIF-1α/HIF-2α inhibitor Acriflavine, and the S1P signaling pathway inhibitor FTY720, in the autochthonous Vhl/Trp53/Rb1 mutant ccRCC mouse model and validated these findings in human ccRCC cell culture models. We show that FTY720 and Acriflavine exhibit therapeutic activity in several different settings of HIF-2α inhibitor resistance. We also identify that HIF-2α inhibition strongly suppresses T cell activation in ccRCC. These findings suggest prioritization of sphingosine pathway inhibitors for clinical testing in ccRCC patients and also suggest that HIF-2α inhibitors may inhibit anti-tumor immunity and might therefore be contraindicated for combination therapies with immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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17 pages, 2731 KiB

Open AccessArticle

Acriflavine, a Potent Inhibitor of HIF-1α, Disturbs Glucose Metabolism and Suppresses ATF4-Protective Pathways in Melanoma under Non-Hypoxic Conditions

by Román Martí-Díaz, María F. Montenegro, Juan Cabezas-Herrera, Colin R. Goding, José Neptuno Rodríguez-López and Luis Sánchez-del-Campo

Cancers 2021, 13(1), 102; https://doi.org/10.3390/cancers13010102 - 31 Dec 2020

Cited by 21 | Viewed by 3913

Abstract

Hypoxia-inducible factor (HIF)-1α is constitutively expressed in melanoma cells under normoxic conditions and its elevated expression correlates with the aggressiveness of melanoma tumors. Here, we used acriflavine, a potent inhibitor of HIF-1α dimerization, as a tool to investigate whether HIF-1α-regulated pathways contribute to the growth of melanoma cells under normoxia. We observed that acriflavine differentially modulated HIF-1α-regulated targets in melanoma under normoxic conditions, although acriflavine treatment resulted in over-expression of vascular endothelial growth factor (VEGF), its action clearly downregulated the expression of pyruvate dehydrogenase kinase 1 (PDK1), a well-known target of HIF-1α. Consequently, downregulation of PDK1 by acrifavine resulted in reduced glucose availability and suppression of the Warburg effect in melanoma cells. In addition, by inhibiting the AKT and RSK2 phosphorylation, acriflavine also avoided protective pathways necessary for survival under conditions of oxidative stress. Interestingly, we show that acriflavine targets activating transcription factor 4 (ATF4) for proteasomal degradation while suppressing the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanocyte development and a melanoma oncogene. Since acriflavine treatment results in the consistent death of melanoma cells, our results suggest that inhibition of HIF-1α function in melanoma could open new avenues for the treatment of this deadly disease regardless of the hypoxic condition of the tumor. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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25 pages, 3792 KiB

Open AccessArticle

Inhibition of HIF-1α by Atorvastatin During ¹³¹I-RTX Therapy in Burkitt’s Lymphoma Model

by Eun-Ho Kim, Hae Young Ko, A Ram Yu, Hyeongi Kim, Javeria Zaheer, Hyun Ji Kang, Young-Cheol Lim, Kyung Deuk Cho, Hyun-Yoo Joo, Min Kyoung Kang, Jae Jun Lee, Seung-Sook Lee, Hye Jin Kang, Sang Moo Lim and Jin Su Kim

Cancers 2020, 12(5), 1203; https://doi.org/10.3390/cancers12051203 - 11 May 2020

Cited by 6 | Viewed by 3473

Abstract

Backgrounds: Radioimmunotherapy (RIT) serves as a targeted therapy for non-Hodgkin lymphomas (NHL). Although HIF(Hypoxia-inducible factors)-1α is an important biomarker during radiation therapy, its role in NHL is unclear. Atorvastatin (ATV) is used as a combination drug for chemotherapy. Methods: We investigated whether ATV downregulated tumor radio-resistance and enhanced the anticancer effect of ¹³¹I-RTX (rituximab) in Raji xenograft mouse models. First, the increased uptake and enhanced therapeutic effect of ¹³¹I-RTX by ATV was confirmed using molecular imaging in Raji xenograft subcutaneous model and orthotropic model with SPECT and IVIS images. Second, we examined the profile of differentially expressed miRNAs using miRNA array. Results: We found that miR-346 inhibited HIF-1α/VEGF (Vascular endothelial growth factor) during ATV combination therapy with ¹³¹I-RTX. The underlying mechanism of ATV involved induction of anti-angiogenesis and radiosensitivity by downregulating HIF-1α in Raji cells. Conclusion: Our findings suggested that combination therapy with ATV and ¹³¹I-RTX is a promising strategy for enhancing the potency of ¹³¹I-RTX therapy in poorly responding patients and those with radio-resistance. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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25 pages, 4530 KiB

Open AccessArticle

Hypoxia-Induced Adaptations of miRNomes and Proteomes in Melanoma Cells and Their Secreted Extracellular Vesicles

by Geoffroy Walbrecq, Odile Lecha, Anthoula Gaigneaux, Miriam R. Fougeras, Demetra Philippidou, Christiane Margue, Milène Tetsi Nomigni, François Bernardin, Gunnar Dittmar, Iris Behrmann and Stephanie Kreis

Cancers 2020, 12(3), 692; https://doi.org/10.3390/cancers12030692 - 14 Mar 2020

Cited by 37 | Viewed by 5331

Abstract

Reduced levels of intratumoural oxygen are associated with hypoxia-induced pro-oncogenic events such as invasion, metabolic reprogramming, epithelial–mesenchymal transition, metastasis and resistance to therapy, all favouring cancer progression. Small extracellular vesicles (EV) shuttle various cargos (proteins, miRNAs, DNA and others). Tumour-derived EVs can be taken up by neighbouring or distant cells in the tumour microenvironment, thus facilitating intercellular communication. The quantity of extracellular vesicle secretion and their composition can vary with changing microenvironmental conditions and disease states. Here, we investigated in melanoma cells the influence of hypoxia on the content and number of secreted EVs. Whole miRNome and proteome profiling revealed distinct expression patterns in normoxic or hypoxic growth conditions. Apart from the well-known miR-210, we identified miR-1290 as a novel hypoxia-associated microRNA, which was highly abundant in hypoxic EVs. On the other hand, miR-23a-5p and -23b-5p were consistently downregulated in hypoxic conditions, while the protein levels of the miR-23a/b-5p-predicted target IPO11 were concomitantly upregulated. Furthermore, hypoxic melanoma EVs exhibit a signature consisting of six proteins (AKR7A2, DDX39B, EIF3C, FARSA, PRMT5, VARS), which were significantly associated with a poor prognosis for melanoma patients, indicating that proteins and/or miRNAs secreted by cancer cells may be exploited as biomarkers. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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21 pages, 954 KiB

Open AccessFeature PaperReview

An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor

by Yukari Shirai, Christalle C. T. Chow, Gouki Kambe, Tatsuya Suwa, Minoru Kobayashi, Itsuki Takahashi, Hiroshi Harada and Jin-Min Nam

Cancers 2021, 13(11), 2813; https://doi.org/10.3390/cancers13112813 - 4 Jun 2021

Cited by 51 | Viewed by 5957

Abstract

Hypoxia, a characteristic feature of solid tumors, is associated with the malignant phenotype and therapy resistance of cancers. Hypoxia-inducible factor 1 (HIF-1), which is responsible for the metazoan adaptive response to hypoxia, has been recognized as a rational target for cancer therapy due to its critical functions in hypoxic regions. In order to efficiently inhibit its activity, extensive efforts have been made to elucidate the molecular mechanism underlying the activation of HIF-1. Here, we provide an overview of relevant research, particularly on a series of HIF-1 activators identified so far and the development of anticancer drugs targeting them. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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18 pages, 1242 KiB

Open AccessReview

HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?

by Diana Gaete, Diego Rodriguez, Deepika Watts, Sundary Sormendi, Triantafyllos Chavakis and Ben Wielockx

Cancers 2021, 13(5), 988; https://doi.org/10.3390/cancers13050988 - 27 Feb 2021

Cited by 19 | Viewed by 4991

Abstract

Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types, and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis, and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that were either recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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17 pages, 957 KiB

Open AccessReview

Specific Inhibition of HIF Activity: Can Peptides Lead the Way?

by Ilias Mylonis, Georgia Chachami and George Simos

Cancers 2021, 13(3), 410; https://doi.org/10.3390/cancers13030410 - 22 Jan 2021

Cited by 16 | Viewed by 3089

Abstract

Reduced oxygen availability (hypoxia) is a characteristic of many disorders including cancer. Central components of the systemic and cellular response to hypoxia are the Hypoxia Inducible Factors (HIFs), a small family of heterodimeric transcription factors that directly or indirectly regulate the expression of hundreds of genes, the products of which mediate adaptive changes in processes that include metabolism, erythropoiesis, and angiogenesis. The overexpression of HIFs has been linked to the pathogenesis and progression of cancer. Moreover, evidence from cellular and animal models have convincingly shown that targeting HIFs represents a valid approach to treat hypoxia-related disorders. However, targeting transcription factors with small molecules is a very demanding task and development of HIF inhibitors with specificity and therapeutic potential has largely remained an unattainable challenge. Another promising approach to inhibit HIFs is to use peptides modelled after HIF subunit domains known to be involved in protein–protein interactions that are critical for HIF function. Introduction of these peptides into cells can inhibit, through competition, the activity of endogenous HIFs in a sequence and, therefore also isoform, specific manner. This review summarizes the involvement of HIFs in cancer and the approaches for targeting them, with a special focus on the development of peptide HIF inhibitors and their prospects as highly-specific pharmacological agents. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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25 pages, 1268 KiB

Open AccessReview

HIF in Nephrotoxicity during Cisplatin Chemotherapy: Regulation, Function and Therapeutic Potential

by Siyao Li, Lu Wen, Xiaoru Hu, Qingqing Wei and Zheng Dong

Cancers 2021, 13(2), 180; https://doi.org/10.3390/cancers13020180 - 7 Jan 2021

Cited by 11 | Viewed by 4243

Abstract

Cisplatin is a highly effective, broad-spectrum chemotherapeutic drug, yet its clinical use and efficacy are limited by its side effects. Particularly, cancer patients receiving cisplatin chemotherapy have high incidence of kidney problems. Hypoxia-inducible factor (HIF) is the “master” transcription factor that is induced under hypoxia to trans-activate various genes for adaptation to the low oxygen condition. Numerous studies have reported that HIF activation protects against AKI and promotes kidney recovery in experimental models of cisplatin-induced acute kidney injury (AKI). In contrast, little is known about the effects of HIF on chronic kidney problems following cisplatin chemotherapy. Prolyl hydroxylase (PHD) inhibitors are potent HIF inducers that recently entered clinical use. By inducing HIF, PHD inhibitors may protect kidneys during cisplatin chemotherapy. However, HIF activation by PHD inhibitors may reduce the anti-cancer effect of cisplatin in tumors. Future studies should test PHD inhibitors in tumor-bearing animal models to verify their effects in kidneys and tumors. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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16 pages, 1752 KiB

Open AccessEditor’s ChoiceReview

Ways into Understanding HIF Inhibition

by Tina Schönberger, Joachim Fandrey and Katrin Prost-Fingerle

Cancers 2021, 13(1), 159; https://doi.org/10.3390/cancers13010159 - 5 Jan 2021

Cited by 27 | Viewed by 8356

Abstract

Hypoxia is a key characteristic of tumor tissue. Cancer cells adapt to low oxygen by activating hypoxia-inducible factors (HIFs), ensuring their survival and continued growth despite this hostile environment. Therefore, the inhibition of HIFs and their target genes is a promising and emerging field of cancer research. Several drug candidates target protein–protein interactions or transcription mechanisms of the HIF pathway in order to interfere with activation of this pathway, which is deregulated in a wide range of solid and liquid cancers. Although some inhibitors are already in clinical trials, open questions remain with respect to their modes of action. New imaging technologies using luminescent and fluorescent methods or nanobodies to complement widely used approaches such as chromatin immunoprecipitation may help to answer some of these questions. In this review, we aim to summarize current inhibitor classes targeting the HIF pathway and to provide an overview of in vitro and in vivo techniques that could improve the understanding of inhibitor mechanisms. Unravelling the distinct principles regarding how inhibitors work is an indispensable step for efficient clinical applications and safety of anticancer compounds. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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13 pages, 1608 KiB

Open AccessReview

Hypoxia Inducible Factors’ Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches

by Quentin Fuchs, Marina Pierrevelcin, Melissa Messe, Benoit Lhermitte, Anne-Florence Blandin, Christophe Papin, Andres Coca, Monique Dontenwill and Natacha Entz-Werlé

Cancers 2020, 12(4), 979; https://doi.org/10.3390/cancers12040979 - 15 Apr 2020

Cited by 19 | Viewed by 4337

Abstract

The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood–brain barrier and all normal brain cells. It is the result of a dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow. However, cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes’ expression involved in cell proliferation, metabolism and angiogenesis and thus, promote tumor expansion, therapeutic resistance and metabolic adaptation. This cellular adaptation implies Hypoxia-Inducible Factors (HIF), namely HIF-1α and HIF-2α. In pediatric high-grade gliomas (pHGGs), several questions remained open on hypoxia-specific role in normal brain during gliomagenesis and pHGG progression, as well how to model it in preclinical studies and how it might be counteracted with targeted therapies. Therefore, this review aims to gather various data about this key extrinsic tumor factor in pHGGs. Full article

(This article belongs to the Special Issue Inhibition of HIFs as an Anti-Cancer Strategy)

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