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Inclusion of the in-chain sulfur in 3-thiaCTU increases the efficiency of mitochondrial targeting and cell killing by anticancer aryl-urea fatty acids.
Rahman, Md Khalilur; Umashankar, Balasubrahmanyam; Choucair, Hassan; Pazderka, Curtis; Bourget, Kirsi; Chen, Yongjuan; Dunstan, Colin R; Rawling, Tristan; Murray, Michael.
Affiliation
  • Rahman MK; Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, and School of Pharmacy, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia.
  • Umashankar B; Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, and School of Pharmacy, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia.
  • Choucair H; Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, and School of Pharmacy, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia.
  • Pazderka C; School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, 2007, Australia.
  • Bourget K; Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, and School of Pharmacy, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia.
  • Chen Y; Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, and School of Pharmacy, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia; Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, Un
  • Dunstan CR; Biomaterials and Tissue Engineering Research Unit, School of Biomedical Engineering, University of Sydney, New South Wales, 2006, Australia.
  • Rawling T; School of Mathematical and Physical Sciences, Faculty of Science, University of Technology Sydney, Ultimo, New South Wales, 2007, Australia.
  • Murray M; Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, and School of Pharmacy, Faculty of Medicine and Health, University of Sydney, New South Wales, 2006, Australia. Electronic address: michael.murray@sydney.edu.au.
Eur J Pharmacol ; 939: 175470, 2023 Jan 15.
Article de En | MEDLINE | ID: mdl-36543287
ABSTRACT
Mitochondria in tumor cells are functionally different from those in normal cells and could be targeted to develop new anticancer agents. We showed recently that the aryl-ureido fatty acid CTU is the prototype of a new class of mitochondrion-targeted agents that kill cancer cells by increasing the production of reactive oxygen species (ROS), activating endoplasmic reticulum (ER)-stress and promoting apoptosis. However, prolonged treatment with high doses of CTU were required for in vivo anti-tumor activity. Thus, new strategies are now required to produce agents that have enhanced anticancer activity over CTU. In the present study we prepared a novel aryl-urea termed 3-thiaCTU, that contained an in-chain sulfur heteroatom, for evaluation in tumor cell lines and in mice carrying tumor xenografts. The principal finding to emerge was that 3-thiaCTU was several-fold more active than CTU in the activation of aryl-urea mechanisms that promoted cancer cell killing. Thus, in in vitro studies 3-thiaCTU disrupted the mitochondrial membrane potential, increased ROS production, activated ER-stress and promoted tumor cell apoptosis more effectively than CTU. 3-ThiaCTU was also significantly more active than CTUin vivo in mice that carried MDA-MB-231 cell xenografts. Compared to CTU, 3-thiaCTU prevented tumor growth more effectively and at much lower doses. These findings indicate that, in comparison to CTU, 3-thiaCTU is an aryl-urea with markedly enhanced activity that could now be suitable for development as a novel anticancer agent.
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Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Acides gras / Antinéoplasiques Limites: Animals / Humans Langue: En Journal: Eur J Pharmacol Année: 2023 Type de document: Article Pays d'affiliation: Australie

Texte intégral: 1 Collection: 01-internacional Base de données: MEDLINE Sujet principal: Acides gras / Antinéoplasiques Limites: Animals / Humans Langue: En Journal: Eur J Pharmacol Année: 2023 Type de document: Article Pays d'affiliation: Australie