PML/RARα Fusion Gene and Response to Retinoic Acid and Arsenic Trioxide Treatment
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
Arsenic trioxide, a naturally occurring chemical element, found in both organic and inorganic compounds, is a poison-become-medicine used for more than 2000 years [59]. Arsenic affects many cellular pathways through different targets. The interaction of trivalent arsenic with the thiol (-SH) groups of cysteine-rich proteins constitutes the basic reaction that underlies the its biological actions [20]. Arsenic promotes degradation of normal PML, as well as the destruction of the PML/RARa fusion protein through its PML moiety. It has been recently shown that arsenic binds directly to -SH groups of PML and generates reactive oxygen species (ROS). The RBCC domain of the PML protein contains cysteine-rich zinc fingers (ZFs) that in normal conditions bind atoms of zinc. The interaction of the ZFs with arsenic leads to slight changes in their structure ultimately causing oligomerisation of PML proteins. Arsenic binds to the cysteine residues of ZFs within the same molecule or by forming ROS-induced disulphide-links with the RBCC domains in the homodimer, facilitating further oligomerisation of PML and PML/RARa. The resultant multimers form matrix-associated NBs that are subsequently SUMOylated by UBC9 enzyme followed by RNF4 ubiquitin E3 ligase-mediated ubiquitination and proteasomal degradation [29, 63] (Fig. 10.1).
Environmental Protection
Lawrence S. Chan, William C. Tang in Engineering-Medicine, 2019
Arsenic is a heavy metal and its contamination in drinking water has affected millions of people worldwide (Ratnaike 2003). The sources of arsenic contamination and toxicity are from both natural geological presence and industrial products, including an anti-neoplastic medicine termed arsenic trioxide that is used for the treatment of promyelocytic leukemia. Absorbed through small intestine following oral ingestion, arsenic exerts its toxicity to humans through inactivation of multiple enzymes (up to 200), targeting particularly those involving DNA synthesis and repair and cellular energy pathways. Two areas of the world that are particularly affected by arsenic toxicity are located in West Bengal, India and Southern Bangladesh, where a total of more than 120 millions of people are exposed to ground water containing arsenic concentration greater than 50 microgram per liter, the maximum permissive limit by the World Health Organization (Ratnaike 2003). In the US, a geographic location of major public health concern is the Millard County, Utah, where residents have been chronically exposed to low to medium concentrations of arsenic in drinking water with associated diseases and cancers (Lewis et al. 1999, Ratnaike 2003).
Inorganic Chemical Pollutants
William J. Rea, Kalpana D. Patel in Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
The primary health effects from the inhalation of the dust of arsenic trioxide and other inorganic arsenic compounds are irritation of the skin and injury to the mucous membranes. However, accumulation can occur with exposure to arsenical pesticides, the most common sources of arsenic today. It can also originate from chickens fed arsenic as a growth stimulator, wells, and treated wood. Also, ulcers and perforation of the nasal septum are not uncommon among arsenic workers. Arsenic has an affinity for keratin. Therefore, fingernails, hair, and skin will be affected by arsenic exposure. Arsenic in a water supply of a Mexican village was shown to cause arthritis and malaise in a large portion of the population. High levels of arsenic have been found in shellfish.
L-Ascorbic Acid and α-Tocopherol Reduces Hepatotoxicity Associated with Arsenic Trioxide Chemotherapy by Modulating Nrf2 and Bcl2 Transcription Factors in Chang liver Cells
Published in Nutrition and Cancer, 2018
Radhakrishnan Chandraprabha Vineetha, Viswanathan Archana, Prakash Binu, Pettamanna Arathi, Raveendran Harikumaran Nair
Arsenic is one of the most deadly metals extensively distributed in the environment. Arsenic trioxide (As2O3), the trivalent form of arsenic, is used in a number of traditional Chinese remedies. As2O3 is reported as an extremely powerful chemotherapeutic agent against acute promyelocytic leukemia (APL) (1). APL is a malignant disorder of the white blood cells which can affect patients of all ages (2); characterized by generation of the promyelocytic leukemia-retinoic acid receptor α (PML-RAR α) fusion gene (3). As2O3 causes apoptosis mainly by the generation of reactive oxygen species (ROS) and oxidative stress (4). ROS such as superoxide, hydroxyl radicals, hydrogen peroxide and nitric oxide are generated during arsenic metabolism in the cells (5) and are capable of damaging a wide variety of cellular macromolecules (6). ROS can damage the cellular machineries like DNA, lipids and proteins and can alter cellular signal transduction such as the activation of transcription factors, the changes of gene expression and induction of apoptosis (7).
Prenatal arsenic exposure interferes in postnatal immunocompetence despite an absence of ongoing arsenic exposure
Published in Journal of Immunotoxicology, 2020
Mainak Chakraborty, Moumita Bhaumik
Arsenic trioxide (As2O3) was purchased from MP Biomedicals (Irvine, CA). Concanavalin A (ConA), and most other general reagents were procured from Sigma (St. Louis, MO). Biotin-conjugated anti-mouse IgG2a and anti-IgG1 were also procured from Sigma. Cell culture reagents and fetal bovine serum (FBS) were purchased from Thermo Fisher Scientific (Waltham, MA) and Sigma. ELISA kits used for analyses of IL-2 and IFNγ were purchased from BD Biosciences (San Jose, CA). PerCP (peridinin-chlorophyll-protein)-conjugated-anti-CD4, APC (allophycocyanin)-anti-CD8, FITC (fluorescein isothiocyanate)-anti-CD25, APC-anti-CD44, FITC-anti-CD69, FITC-anti-CD11b, and PE (phycoerythrin)-anti-I-Ad were purchased from eBiosciences (San Diego, CA).
Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach
Published in Critical Reviews in Toxicology, 2019
Joyce S. Tsuji, Ellen T. Chang, P. Robinan Gentry, Harvey J. Clewell, Paolo Boffetta, Samuel M. Cohen
The Efremenko et al. (2015) study was conducted as a complementary experiment to the Yager et al. (2013) study; the concentrations used in Efremenko et al. (2015) were the same as those in the human urothelial study (Yager et al. 2013). In addition to the arsenical trivalent mixture exposures, exposures to arsenic trioxide were also performed to compare responses for exposures of lung epithelial cells at the apical membrane from inhalation and exposures at the basal membrane from oral exposure. Similar analyses of the gene expression results were conducted as those in the Yager et al. (2013) study for urothelial cells, focusing on those genes expressed most in common among cells from three individuals. Benchmark dose analysis confirmed similarity in the concentration-response relationship between lung and bladder epithelial cells, with comparable benchmark dose estimates across tissue types for the trivalent mixtures, as well as comparable benchmark dose estimates following exposures of lung cells to either the trivalent mixture or arsenic trioxide. The consistency of the genomic responses in human primary cells from two different tissues (bladder and lung) and for two different trivalent arsenic exposures (arsenite and its trivalent metabolites vs. arsenite alone) supports the usefulness of this data to characterize the dose response for the cellular effects of trivalent inorganic arsenic.
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