Targeting Hypoxia: Revival of Old Remedies

Vilaplana-Lopera, Nuria; Besh, Maxym; Moon, Eui Jung

doi:10.3390/biom11111604

Cited by 10 publications

(9 citation statements)

References 188 publications

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“…13,14 For more than a century, extensive efforts have been made to address tumor hypoxia in both experimental and clinical settings. 15 The key is to develop therapies that aim to target the hypoxic environment and improve intratumoral oxygenation to inhibit tumor progression and treatment resistance. To target hypoxic cells, inhibitors of hypoxia-related pathways, such as HIFs and mammalian target of rapamycin (mTOR), have been developed.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia signaling in cancer: Implications for therapeutic interventions

Zhuang

Liu

et al. 2023

MedComm

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Hypoxia is a persistent physiological feature of many different solid tumors and a key driver of malignancy, and in recent years, it has been recognized as an important target for cancer therapy. Hypoxia occurs in the majority of solid tumors due to a poor vascular oxygen supply that is not sufficient to meet the needs of rapidly proliferating cancer cells. A hypoxic tumor microenvironment (TME) can reduce the effectiveness of other tumor therapies, such as radiotherapy, chemotherapy, and immunotherapy. In this review, we discuss the critical role of hypoxia in tumor development, including tumor metabolism, tumor immunity, and tumor angiogenesis. The treatment methods for hypoxic TME are summarized, including hypoxia‐targeted therapy and improving oxygenation by alleviating tumor hypoxia itself. Hyperoxia therapy can be used to improve tissue oxygen partial pressure and relieve tumor hypoxia. We focus on the underlying mechanisms of hyperoxia and their impact on current cancer therapies and discuss the prospects of hyperoxia therapy in cancer treatment.

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Section: Introductionmentioning

confidence: 99%

“…For more than a century, extensive efforts have been made to address tumor hypoxia in both experimental and clinical settings 15 . The key is to develop therapies that aim to target the hypoxic environment and improve intratumoral oxygenation to inhibit tumor progression and treatment resistance.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia signaling in cancer: Implications for therapeutic interventions

Zhuang

Liu

et al. 2023

MedComm

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“…As it was mentioned by Tharmalingham, H. et al [ 64 ], the use of nimorazole as a radiosensitizer was a standard practice in Denmark alone, as Danish research confirmed its safety in the treatment of, e.g., supraglottic and pharynx tumors. Recently, new clinical trials with nimorazole in Denmark and the UK have also been reported, but it is still necessary to assess whether this drug directly changes the oxygenation status of patient tumors [ 65 ].…”

Section: Hypoxia-activated Prodrugs (Haps)mentioning

confidence: 99%

Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off–on Probes for Hypoxia Imaging

Janczy-Cempa

Mazuryk

Kania

et al. 2022

Cancers

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Hypoxia is one of the hallmarks of the tumor microenvironment and can be used in the design of targeted therapies. Cellular adaptation to hypoxic stress is regulated by hypoxia-inducible factor 1 (HIF-1). Hypoxia is responsible for the modification of cellular metabolism that can result in the development of more aggressive tumor phenotypes. Reduced oxygen concentration in hypoxic tumor cells leads to an increase in oxidoreductase activity that, in turn, leads to the activation of hypoxia-activated prodrugs (HAPs). The same conditions can convert a non-fluorescent compound into a fluorescent one (fluorescent turn off–on probes), and such probes can be designed to specifically image hypoxic cancer cells. This review focuses on the current knowledge about the expression and activity of oxidoreductases, which are relevant in the activation of HAPs and fluorescent imaging probes. The current clinical status of HAPs, their limitations, and ways to improve their efficacy are briefly discussed. The fluorescence probes triggered by reduction with specific oxidoreductase are briefly presented, with particular emphasis placed on those for which the correlation between the signal and enzyme expression determined with biochemical methods is achievable.

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“…Hypoxia-activated prodrugs (HAPs) are bioreductive drugs that are selectively reduced by reductases under hypoxic conditions to form cytotoxic compounds that kill hypoxic tumor cells (Denny, 2000;Denny, 2010;Hunter et al, 2016;Phillips, 2016;Baran and Konopleva, 2017;Mistry et al, 2017;Jackson et al, 2019;Li et al, 2021a;Anduran et al, 2021;Li et al, 2021b;Codony and Tavassoli, 2021). This bio-reductive process is inhibited by oxygen preventing the complete reduction of the compound into its active form (Vilaplana-Lopera et al, 2021). In other words, HAPs should not be toxic for normal oxygenated tissues.…”

Section: Prodrugs Activated In Hypoxic Cellsmentioning

confidence: 99%

The Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia

Gallez

2022

Front. Pharmacol.

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Hypoxia is a common feature of solid tumors that contributes to angiogenesis, invasiveness, metastasis, altered metabolism and genomic instability. As hypoxia is a major actor in tumor progression and resistance to radiotherapy, chemotherapy and immunotherapy, multiple approaches have emerged to target tumor hypoxia. It includes among others pharmacological interventions designed to alleviate tumor hypoxia at the time of radiation therapy, prodrugs that are selectively activated in hypoxic cells or inhibitors of molecular targets involved in hypoxic cell survival (i.e., hypoxia inducible factors HIFs, PI3K/AKT/mTOR pathway, unfolded protein response). While numerous strategies were successful in pre-clinical models, their translation in the clinical practice has been disappointing so far. This therapeutic failure often results from the absence of appropriate stratification of patients that could benefit from targeted interventions. Companion diagnostics may help at different levels of the research and development, and in matching a patient to a specific intervention targeting hypoxia. In this review, we discuss the relative merits of the existing hypoxia biomarkers, their current status and the challenges for their future validation as companion diagnostics adapted to the nature of the intervention.

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Targeting Hypoxia: Revival of Old Remedies

Cited by 10 publications

References 188 publications

Hypoxia signaling in cancer: Implications for therapeutic interventions

Hypoxia signaling in cancer: Implications for therapeutic interventions

Significance of Specific Oxidoreductases in the Design of Hypoxia-Activated Prodrugs and Fluorescent Turn off–on Probes for Hypoxia Imaging

The Role of Imaging Biomarkers to Guide Pharmacological Interventions Targeting Tumor Hypoxia

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