Functional Profiling Identifies Determinants of Arsenic Trioxide Cellular Toxicity. 2019

Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida.

Arsenic exposure is a worldwide health concern associated with an increased risk of skin, lung, and bladder cancer but arsenic trioxide (AsIII) is also an effective chemotherapeutic agent. The current use of AsIII in chemotherapy is limited to acute promyelocytic leukemia (APL). However, AsIII was suggested as a potential therapy for other cancer types including chronic myeloid leukemia (CML), especially when combined with other drugs. Here, we carried out a genome-wide CRISPR-based approach to identify modulators of AsIII toxicity in K562, a human CML cell line. We found that disruption of KEAP1, the inhibitory partner of the key antioxidant transcription factor Nrf2, or TXNDC17, a thioredoxin-like protein, markedly increased AsIII tolerance. Loss of the water channel AQP3, the zinc transporter ZNT1 and its regulator MTF1 also enhanced tolerance to AsIII whereas loss of the multidrug resistance protein ABCC1 increased sensitivity to AsIII. Remarkably, disruption of any of multiple genes, EEFSEC, SECISBP2, SEPHS2, SEPSECS, and PSTK, encoding proteins involved in selenocysteine metabolism increased resistance to AsIII. Our data suggest a model in which an intracellular interaction between selenium and AsIII may impact intracellular AsIII levels and toxicity. Together this work revealed a suite of cellular components/processes which modulate the toxicity of AsIII in CML cells. Targeting such processes simultaneously with AsIII treatment could potentiate AsIII in CML therapy.

UI MeSH Term Description Entries
D002470 Cell Survival The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. Cell Viability,Cell Viabilities,Survival, Cell,Viabilities, Cell,Viability, Cell
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000072669 Gene Editing Genetic engineering or molecular biology techniques that involve DNA REPAIR mechanisms for incorporating site-specific modifications into a cell's genome. Base Editing,Genome Editing,Editing, Base,Editing, Gene,Editing, Genome
D000077237 Arsenic Trioxide An inorganic compound with the chemical formula As2O3 that is used for the treatment of ACUTE PROMYELOCYTIC LEUKEMIA in patients who have relapsed from, or are resistant to, conventional drug therapy. Arsenic Oxide (As2O3),Arsenic Oxide (As4O6),Arsenic(III) Oxide,Arsenolite,Arsenous Anhydride,As2O3,As4O6,Diarsenic Trioxide,Naonobin,Tetra-Arsenic Hexaoxide,Tetra-Arsenic Oxide,Tetraarsenic Hexaoxide,Tetraarsenic Oxide,Trisenox,Trixenox,Tetra Arsenic Hexaoxide,Tetra Arsenic Oxide
D000970 Antineoplastic Agents Substances that inhibit or prevent the proliferation of NEOPLASMS. Anticancer Agent,Antineoplastic,Antineoplastic Agent,Antineoplastic Drug,Antitumor Agent,Antitumor Drug,Cancer Chemotherapy Agent,Cancer Chemotherapy Drug,Anticancer Agents,Antineoplastic Drugs,Antineoplastics,Antitumor Agents,Antitumor Drugs,Cancer Chemotherapy Agents,Cancer Chemotherapy Drugs,Chemotherapeutic Anticancer Agents,Chemotherapeutic Anticancer Drug,Agent, Anticancer,Agent, Antineoplastic,Agent, Antitumor,Agent, Cancer Chemotherapy,Agents, Anticancer,Agents, Antineoplastic,Agents, Antitumor,Agents, Cancer Chemotherapy,Agents, Chemotherapeutic Anticancer,Chemotherapy Agent, Cancer,Chemotherapy Agents, Cancer,Chemotherapy Drug, Cancer,Chemotherapy Drugs, Cancer,Drug, Antineoplastic,Drug, Antitumor,Drug, Cancer Chemotherapy,Drug, Chemotherapeutic Anticancer,Drugs, Antineoplastic,Drugs, Antitumor,Drugs, Cancer Chemotherapy
D013997 Time Factors Elements of limited time intervals, contributing to particular results or situations. Time Series,Factor, Time,Time Factor
D015398 Signal Transduction The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D015464 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Clonal hematopoetic disorder caused by an acquired genetic defect in PLURIPOTENT STEM CELLS. It starts in MYELOID CELLS of the bone marrow, invades the blood and then other organs. The condition progresses from a stable, more indolent, chronic phase (LEUKEMIA, MYELOID, CHRONIC PHASE) lasting up to 7 years, to an advanced phase composed of an accelerated phase (LEUKEMIA, MYELOID, ACCELERATED PHASE) and BLAST CRISIS. Granulocytic Leukemia, Chronic,Leukemia, Granulocytic, Chronic,Leukemia, Myelocytic, Chronic,Leukemia, Myelogenous, Chronic,Leukemia, Myeloid, Chronic,Myelocytic Leukemia, Chronic,Myelogenous Leukemia, Chronic,Myeloid Leukemia, Chronic,Leukemia, Chronic Myelogenous,Leukemia, Chronic Myeloid,Leukemia, Myelogenous, Ph1 Positive,Leukemia, Myelogenous, Ph1-Positive,Leukemia, Myeloid, Ph1 Positive,Leukemia, Myeloid, Ph1-Positive,Leukemia, Myeloid, Philadelphia Positive,Leukemia, Myeloid, Philadelphia-Positive,Myelogenous Leukemia, Ph1-Positive,Myeloid Leukemia, Ph1-Positive,Myeloid Leukemia, Philadelphia-Positive,Chronic Granulocytic Leukemia,Chronic Granulocytic Leukemias,Chronic Myelocytic Leukemia,Chronic Myelocytic Leukemias,Chronic Myelogenous Leukemia,Chronic Myelogenous Leukemias,Chronic Myeloid Leukemia,Chronic Myeloid Leukemias,Granulocytic Leukemias, Chronic,Leukemia, Chronic Granulocytic,Leukemia, Chronic Myelocytic,Leukemia, Ph1-Positive Myelogenous,Leukemia, Ph1-Positive Myeloid,Leukemia, Philadelphia-Positive Myeloid,Leukemias, Chronic Granulocytic,Leukemias, Chronic Myelocytic,Leukemias, Chronic Myelogenous,Leukemias, Chronic Myeloid,Leukemias, Ph1-Positive Myelogenous,Leukemias, Ph1-Positive Myeloid,Leukemias, Philadelphia-Positive Myeloid,Myelocytic Leukemias, Chronic,Myelogenous Leukemia, Ph1 Positive,Myelogenous Leukemias, Chronic,Myelogenous Leukemias, Ph1-Positive,Myeloid Leukemia, Ph1 Positive,Myeloid Leukemia, Philadelphia Positive,Myeloid Leukemias, Chronic,Myeloid Leukemias, Ph1-Positive,Myeloid Leukemias, Philadelphia-Positive,Ph1-Positive Myelogenous Leukemia,Ph1-Positive Myelogenous Leukemias,Ph1-Positive Myeloid Leukemia,Ph1-Positive Myeloid Leukemias,Philadelphia-Positive Myeloid Leukemia,Philadelphia-Positive Myeloid Leukemias
D015973 Gene Expression Regulation, Leukemic Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in leukemia. Leukemic Gene Expression Regulation,Regulation of Gene Expression, Leukemic,Regulation, Gene Expression, Leukemic

Related Publications

Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
May 2018, ACS omega,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
September 2001, Blood,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
September 2001, Blood,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
February 2013, European review for medical and pharmacological sciences,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
January 2002, Cardiovascular toxicology,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
January 2009, Cancer genomics & proteomics,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
January 2001, Clinical journal of oncology nursing,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
July 2008, Expert opinion on pharmacotherapy,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
November 2005, Mutation research,
Amin Sobh, and Alex Loguinov, and Gulce Naz Yazici, and Rola S Zeidan, and Abderrahmane Tagmount, and Nima S Hejazi, and Alan E Hubbard, and Luoping Zhang, and Chris D Vulpe
November 2019, Journal of applied toxicology : JAT,
Copied contents to your clipboard!