China
Africa
Explore chapters and articles related to this topic
Ascorbate and the Hypoxic Response in Cancer
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Christina Wohlrab, Caroline Kuiper, Gabi U. Dachs
One of the main mechanisms by which HIF-1 promotes resistance to both radiation and chemotherapy is the activation of DNA repair pathways [51]. Indeed, HIF-1 controls expression of most of the cell's DNA repair genes, including poly-ADP-ribose polymerase (PARP-1), XPA (part of base excision repair), ataxia telangiectasia mutated (ATM), and DNA-dependent protein kinase (DNA-PK) [52,53]. In addition, resistance to cancer therapies are induced via HIF-1-regulated metabolic reprogramming and modulation of cell death pathways, namely, inhibition of apoptosis and activation of autophagy [51].
Cytotoxic Phenanthridone Alkaloid Constituents of the Amaryllidaceae
Published in Spyridon E. Kintzios, Maria G. Barberaki, Evangelia A. Flampouri, Plants That Fight Cancer, 2019
Jerald J. Nair, Johannes van Staden
There are compelling pieces of evidence pointing towards the involvement of nitric oxide (NO) in the pathophysiology of cancer (Xu et al. 2002). Increased cellular NO generation could result in increased mutant p53 cellular activity which would contribute to tumor angiogenesis via upregulation of VEGF (vascular endothelial growth factor) (Xu et al. 2002). In addition, NO may modulate tumor DNA repair mechanisms by upregulating tumor suppressor protein p53, poly-ADP ribose polymerase (PARP), and DNA-dependent protein kinase (DNA-PK) (Xu et al. 2002). For these reasons, the discovery of novel cellular NO modulators is of significant interest in the cancer chemotherapy arena. Of the Amaryllidaceae alkaloids examined for NO modulatory effects, narciclasine (11) exhibited potent activity (IC50 0.01 µM) against NO production in LPS-stimulated mouse RAW264 macrophages (Yamazaki and Kawano 2011).
Irradiation-induced damage and the DNA damage response
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Conchita Vens, Marianne Koritzinsky, Bradly G. Wouters
H2AX is a variant of histone H2A, a component of the core nucleosome structure around which DNA is packaged. Starting within a few minutes of DSB formation, H2AX becomes phosphorylated at the DSB site. The phosphorylated form of H2AX is termed γH2AX. The phosphorylation of H2AX proteins spreads over relatively large chromatin regions (megabases) in both directions of the DSB, an event that is regulated by an additional protein called MDC1. MDC1 acts as an adaptor by directly binding to both ATM and to γH2AX and in this way is able to amplify ATM-mediated γH2AX in both directions of the break. This amplification significantly alters the chromatin structure around the DSB and is thought to be important for access of other DNA repair proteins to the break. The presence of large areas of γH2AX around a single DSB facilitates the detection of γH2AX foci using microscopy and specific antibodies. In addition to ATM, two other kinases have been shown to phosphorylate H2AX at the sites of DSBs: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and AT-related (ATR) protein (7).
Mitochondrial dysfunction and mitochondrion-targeted therapeutics in liver diseases
Published in Journal of Drug Targeting, 2021
Li Xiang, Yaru Shao, Yuping Chen
p53 achieves the MQC for hepatocytes by regulating mitochondrial fission and mitophagy [103]. It was seen to be phosphorylated and activated by the DNA-dependent protein kinase (DNA-PK) essential for double strands DNA breaks (DSB) repair and caused more apoptosis in the ionizing-radiated HCC cells [104]. In diet-induced NAFLD hepatocytes, p53 propelled mitochondrial fission via supporting Drp1 movement and arrested mitophagy via downregulating Bnip3. These roles were proved to be mediated by a signalling pathway consisting of DNA-PKcs, p53 and the orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) that is phosphorylated by DNA-PK and then translocates to the DSB foci for repairing; while either the genetic deletion of NR4A1 or DN-PKcs or melatonin supplementation could significantly restore mitochondrial normality and liver function in NAFLD [105]. Consistently, deleting DNA-PKcs gene also inhibited this signalling pathway and protected the liver from the ethanol-induced hepatic and mitochondrial damage [106]. In one early study, melatonin enhanced the mitophagy and mitochondrial biogenesis of hepatocytes and alleviated the CCl4-induced chronic liver fibrosis in rats [67]. Furthermore, it was proved to activate the SIRT1-PGC-1 α pathway to downregulate Drp1 and inhibit excessive mitochondrial fission [107].
Radiosensitizing Potential of Curcumin in Different Cancer Models
Published in Nutrition and Cancer, 2020
Mechanisms that suppress tumorigenesis after irradiation treatment are generally diverse and interrelated, involving modulation of cellular signal transduction pathways that ultimately lead to cell death (1, 33). Ionizing radiation enhances production of free radicals, reactive oxygen species (ROS), which play a crucial role in cell signaling and cause damage to the DNA inducing double-stranded breaks (2, 34). After that, DNA damage response pathway is actuated by activating the proteins related to DNA reparation, ie., ataxia telangiectasia mutated, ATM and DNA-dependent protein kinase, DNA-PK (22, 34). Therefore, use of natural phytochemicals that augment ROS generation and suppress DNA repair machinery could be important in regulation of radiation-induced cell death (2, 22). However, it is well accepted that due to higher basal production of ROS, the intrinsic level of oxidative stress is greater in malignant cells than normal cells, allowing cancer cells to develop enhanced endogenous antioxidant capacity that makes them more resistant to exogenous oxidative attacks (14, 24,25). The upregulation of antioxidant enzymes, such as thioredoxin reductase-1 (TxnRd1), has been indeed reported in numerous human tumor types (14). Thus, besides potentiation of ROS production, inhibition of key antioxidant proteins by nontoxic natural agents could also contribute to augmentation of radioresponse in cancerous cells.
Establishing mechanisms affecting the individual response to ionizing radiation
Published in International Journal of Radiation Biology, 2020
Dietrich Averbeck, Serge Candéias, Sudhir Chandna, Nicolas Foray, Anna A. Friedl, Siamak Haghdoost, Penelope A. Jeggo, Katalin Lumniczky, Francois Paris, Roel Quintens, Laure Sabatier
DNA has long been identified as the major cellular target with DNA double strand breaks (DSBs) being the most biologically significant lesion determining survival following radiation exposure. The response to DSBs encompasses pathways of DNA repair and a signal transduction response, which interface but are mechanistically distinct (Shibata and Jeggo 2014). Collectively, this is called the DNA damage response (DDR). Any variation in efficiency of the DDR and its impact on the fidelity of repair is expected to affect cell survival and/or genomic stability. The most significant DNA repair pathway is DNA non-homologous end-joining (NHEJ) (Chang et al. 2017). In brief, this pathway involves the binding of the Ku protein to DNA ends, which protects them from degradation. This is followed by recruitment of the DNA dependent protein kinase catalytic subunit (DNA-PKcs) (generating the DNA-PK complex) and finally, ligation by a complex involving DNA ligase IV, XRCC4 and XLF (see (Shibata and Jeggo 2014) for a review).