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Introduction to Cancer, Conventional Therapies, and Bionano-Based Advanced Anticancer Strategies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Hypoxic stress has several effects on cells, such as metabolic changes and altered cell growth [77]. A major driver of cancer angiogenesis is hypoxia [65]. Reducing hypoxia is a possible target that can help control cancer [77]. In response to low oxygenation, cells upregulate the hypoxia-inducible factor (HIF), which is a transcription factor that has a role in coordinating an adaptive response within the pathophysiological and physiological range [78]. Under conditions of hypoxia, HIF is able to activate the transcription of several genes that have a role in maintaining oxygen homeostasis. HIF influences the expression of target genes involved in cell metabolism, invasiveness, angiogenesis, and erythropoiesis. Studies have shown that HIF has been correlated with poor outcomes in patients affected by cancer [79].
Hypoxia-Responsive Nanomedicines
Published in Lin Zhu, Stimuli-Responsive Nanomedicine, 2021
Federico Perchea, Kanjiro Miyata
Response to hypoxia is coordinated by the transcription factors Hypoxia Inducible Factors (HIFs), considered as the molecular sensors of hypoxia [20, 21]. HIFs are dimeric proteins with, a β unit (HIF-1β, HIF-2β), and a a subunit (HIF-1α, HIF-2α, HIF-3α) [22]. Response to oxygen tension is achieved by the control of HIF-α stability in the presence of oxygen via hydroxylation of the prolines in the ODDD (Oxygen-Dependent Degradation Domain) by prolyl hydroxylases (PHDs), an hydroxylation resulting in rapid ubiquitin-mediated HIF-a proteasome processing under normoxia [23]. Under hypoxia, a subunits get stabilized by inhibition of PHDs by reactive oxygen species (ROS), a stabilization allowing HIF-a translocation to the nucleus where it dimerizes with HIF-0 to control gene transcription of more than 200 genes containing hypoxia responsive elements (HRE) in their promoter [23]. Fine response to hypoxia gradients is achieved by different O2-dependent stabilization thresholds for HIF-1a (0–2% O2) and HIF-2a (2–5% O2) [24]. In addition to induction of the transcription of genes containing HRE, hypoxia also controls cellular metabolism by oxygen-dependent expression of a set of miRNA defined as hypoxia regulated miRNA [25, 26].
Drug Targeting: Principles and Applications
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Drug Delivery Approaches and Nanosystems, 2017
Ruslan G. Tuguntaev, Ahmed Shaker Eltahan, Satyajeet S. Salvi, Xing-Jie Liang
Hypoxia is another hallmark of malignant progression. It is well established, that hypoxic cells are more resistant to anticancer therapy (Kizaka-Kondoh et al., 2003). Under low oxygen tension conditions, the cytotoxicity of drugs whose activity is mediated by free radicals is decreased (Trédan et al., 2007). Moreover, low oxygen concentration decreases cell proliferation and as a consequence, the activity of these drugs that selectively target highly proliferating cells is also reduced. Therefore, hypoxia-targeted therapy is-based on two main approaches. The first one is to enhance oxygen concentration in tumor tissues by improving oxygenation and combining it with chemotherapy (Kizaka-Kondoh et al., 2003). The second approach involves targeting the hypoxic tumor microenvironment. Hypoxia-targeted strategy is-based on exploitation of bio-reductive prodrugs or HIF-1α-targeted compounds (Guise et al., 2014; Chen et al., 2003). Bioreductive prodrugs are agents, which under hypoxic conditions, turns into active cytotoxic metabolites by enzymatic reduction. For example, tirapazamine, a bireductive prodrug, has been activated under hypoxic conditions and reduced form of this prodrug causes DNA damage (Reddy et al., 2009). Other effective strategy is targeting the HIF-1α signaling pathway components. For instance, by targeting HIF antisense mRNA with EZN-2968 or FRAP/mTOR by rapamycin, can block HIF-1α function and can attenuate tumor growth (Kizaka-Kondoh et al., 2003; Wilson et al., 2011).
The study on the inhibitory mechanism of JTZ-951 and its analogue against prolyl hydroxylase-2 to mediate the response to hypoxia in the process of sports
Published in Molecular Physics, 2021
Tao Li, Song Wang, Hao Zhang, Jiankang Yu
Recent studies showed that hypoxia inducible factor (HIF) is the critical factor for the expression of EPO in the red blood cell system. HIF consists of two subunits, an oxygen regulated α subunit (HIF-α) and a constitutively expressed β subunit (HIF-β). HIF modulates the various gene expression including EPO, angiogenesis, vascular tone, glucose metabolism, cell proliferation [4,5]. The hypoxia-associated transcription activity of HIF can be regulated metabolically by the dioxygenases, namely prolyl hydroxylases (PHD) having three subtypes (PHD 1-3) [6,7]. The C4 trans hydroxylation of HIF-α at PRO-402 and PRO-564 are realised based on the transcription activity of HIF by using 2-oxoglutarate (2-OG), O2 and Fe(II) as cofactors [8]. This mechanism shows that the hydroxylation of HIF-α is inhibited by PHDs during hypoxia in the process of sports, leading to the stabilisation of HIF-α and adaptation to hypoxia [9,10]. Thus, inhibitors targeting to PHDs may increase the EPO levels due to the stabilisation of HIF-α. Furthermore, it has been widely believed that PHD-2 is the key factor in controlling the transcription of HIF among three PHDs [11]. In fact, PHD-2 has become the promising target to mediate the level of EPO for the HIF-related diseases recently [12]. Furthermore, based on the crystallography method, the structural information of PHD-2 was explored. The binding sites of substrate and hydroxylation site were identified [13–15].
Detoxifying effects of optimal hyperoxia (40% oxygenation) exposure on benzo[a]pyrene-induced toxicity in human keratinocytes
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Yong Chan Kwon, Hyung Sik Kim, Byung-Mu Lee
In this study, HIF-1α was measured to assess O2 levels within the cell (Chandel and Budinger 2007). HIF-1α is a protein that is expressed dependent upon O2 concentrations. In particular, it is a protein that is commonly detected in hypoxic conditions. The expression of this protein was reduced with increasing O2 levels and did not appear to be markedly affected by the presence of B[a]P in HaCat cells (Figure 4b).
Effects of intermittent hypoxic training performed at high hypoxia level on exercise performance in highly trained runners
Published in Journal of Sports Sciences, 2018
Anthony M. J. Sanchez, Fabio Borrani
Chronic adaptations to altitude and normobaric hypoxic training include muscle remodeling and the modulation of central factors such as ventilation, haemodynamics or neural factors. The most recognized effects of training in hypoxia are growth of mitochondrial density, increased oxidative enzyme activity, enhanced capillary thickness, and generally a shift from fat and muscle glycogen to blood glucose combustion (Bailey & Davies, 1997; Böning, 1997; Flaherty et al., 2016). In addition, a transient increase in hemoglobin concentration and hematocrit can be observed, especially for acclimatisation to spending many weeks at altitude or in hypoxia (De Smet et al., 2017; Park et al., 2016; Wehrlin, Marti, & Hallén, 2016; Woods et al., 2017). However, the duration of hypoxic exposure appears too small to induce hematological adaptations in hypoxic training interventions (Constantini, Wilhite, & Chapman, 2017; Park, Nam, Tanaka, & Lee, 2016). From a molecular viewpoint, the hypoxia-inducible factor (HIF-1) induces transcription of the erythropoietin (EPO) gene and other molecules involved in angiogenesis in response to hypoxia (Prabhakar & Semenza, 2012), while it is quickly degraded by the ubiquitin-proteasome system in normoxia (Cheng, Kang, Zhang, & Yeh, 2007; Wilber, Stray-Gundersen, & Levine, 2007). HIF-1 is also involved in the improvement of tissue function during low oxygen availability through increased expression of glycolytic enzymes and glucose transporters. Furthermore, recent data strongly suggests that the HIF-1α response is blunted in response to long-term exercise training which promotes enhanced oxidative metabolism (Lindholm & Rundqvist, 2016). According to the degree of hypoxia and the duration of exposure, the effects of IHT on performance seem more related to skeletal muscle adaptations than to systemic responses (Hoppeler & Vogt, 2001; Lundby, Calbet, & Robach, 2009; Park et al., 2016; Villa et al., 2005; Vogt et al., 2001; Zoll et al., 2006). Moreover, with IHT, even if athletes are under hypoxic stress, the training-related stress is limited due to the diminution of training load. “IHNT” is an interval training modality where high-intensity exercise periods are conducted under hypoxia, while the recovery periods are in normoxia. Performing recoveries in normoxia during IHNT allows completion of greater workloads during the sessions (e.g. more repetitions), especially when the hypoxic stimulus is the key. However, to our knowledge, this variant of IHT has not yet been assessed in athletes. Previous studies have only shown that this method is successful in patients, especially among those with neurological disorders, but were completed with a lower hypoxic stimulus (Astorino, Harness, & White, 2015).