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Enhanced cytotoxici...
Enhanced cytotoxicity of a novel family of ATPase inhibitors in colorectal cancer cells with high NAT2 activity
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- Zhang, Xiaonan (author)
- Uppsala universitet,Cancerprecisionsmedicin
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- Akcan, Ece (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Correia, Mario S. P. (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för kemi - BMC
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- Rameika, Natallia (author)
- Uppsala universitet,Cancerprecisionsmedicin
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- Kundu, Snehangshu (author)
- Uppsala universitet,Cancerprecisionsmedicin
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- Stoimenov, Ivaylo (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Rendo, Verónica (author)
- Uppsala universitet,Cancerprecisionsmedicin,Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA.
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- Eriksson, Anna U. (author)
- Umeå universitet,Kemiska institutionen,Umeå Univ, Dept Chem, CBCS, KBC C4, SE-90187 Umeå, Sweden.
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- Haraldsson, Martin (author)
- Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden,Karolinska Inst, Chem Biol Consortium Sweden CBCS, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
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- Globisch, Daniel (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Analytisk kemi
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- Sjöblom, Tobias (author)
- Uppsala universitet,Cancerprecisionsmedicin
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(creator_code:org_t)
- Elsevier, 2022
- 2022
- English.
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In: Biochemical Pharmacology. - : Elsevier. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 203
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Abstract
Subject headings
Close
- Loss of heterozygosity (LOH) is a hallmark feature of cancer genomes that reduces allelic variation, thereby creating tumor specific vulnerabilities which could be exploited for therapeutic purposes. We previously reported that loss of drug metabolic arylamine N-acetyltransferase 2 (NAT2) activity following LOH at 8p22 could be targeted for collateral lethality anticancer therapy in colorectal cancer (CRC). Here, we report a novel compound CBK034026C that exhibits specific toxicity towards CRC cells with high NAT2 activity. Connectivity Map analysis revealed that CBK034026C elicited a response pattern related to ATPase inhibitors. Similar to ouabain, a potent inhibitor of the Na+/K+-ATPase, CBK034026C activated the Nf-kB pathway. Further metabolomic profiling revealed downregulation of pathways associated with antioxidant defense and mitochondrial metabolism in CRC cells with high NAT2 activity, thereby weakening the protective response to oxidative stress induced by CBK034026C. The identification of a small molecule targeting metabolic vulnerabilities caused by NAT2 activity provides novel avenues for development of anticancer agents.
Subject headings
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
Keyword
- Arylamine N acetyltransferase 2 (NAT2)
- ATPase inhibitors
- Colorectal cancer
- Loss of heterozygosity (LOH)
- Nf-kB pathway
- Small molecule therapeutics
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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Zhang, Xiaonan
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Akcan, Ece
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Correia, Mario S ...
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Rameika, Natalli ...
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Kundu, Snehangsh ...
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Stoimenov, Ivayl ...
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show more...
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Rendo, Verónica
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Eriksson, Anna U ...
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Haraldsson, Mart ...
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Globisch, Daniel
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Sjöblom, Tobias
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show less...
- About the subject
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmacology and ...
- Articles in the publication
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Biochemical Phar ...
- By the university
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Umeå University
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Uppsala University
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Karolinska Institutet