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, MK; Umashankar, B; Choucair, H; Pazderka, C; Bourget, K; Chen, Y; Dunstan, CR; Rawling, T; Murray, M

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, MK Umashankar, B Choucair, H Pazderka, C

Bourget, K Chen, Y Dunstan, CR Rawling, T

Murray, M

Permalink

Publisher:: ELSEVIER
Publication Type:: Journal Article
Citation:: Eur J Pharmacol, 2023, 939, pp. 175470
Issue Date:: 2023-01-15

Closed Access

	Filename	Description	Size
	1-s2.0-S0014299922007312-main.pdf	Published version	8.66 MB		View/Open

Copyright Clearance Process

Recently Added
In Progress
Closed Access

This item is closed access and not available.

Full metadata record

Field	Value	Language
dc.contributor.author	Rahman, MK
dc.contributor.author	Umashankar, B
dc.contributor.author	Choucair, H
dc.contributor.author	Pazderka, C https://orcid.org/0000-0002-6070-6481
dc.contributor.author	Bourget, K
dc.contributor.author	Chen, Y
dc.contributor.author	Dunstan, CR
dc.contributor.author	Rawling, T https://orcid.org/0000-0002-6624-6586
dc.contributor.author	Murray, M
dc.date.accessioned	2024-02-06T03:13:47Z
dc.date.available	2022-12-15
dc.date.available	2024-02-06T03:13:47Z
dc.date.issued	2023-01-15
dc.identifier.citation	Eur J Pharmacol, 2023, 939, pp. 175470
dc.identifier.issn	0014-2999
dc.identifier.issn	1879-0712
dc.identifier.uri	http://hdl.handle.net/10453/175354
dc.description.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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	ELSEVIER
dc.relation.ispartof	Eur J Pharmacol
dc.relation.isbasedon	10.1016/j.ejphar.2022.175470
dc.rights	info:eu-repo/semantics/closedAccess
dc.subject	0801 Artificial Intelligence and Image Processing, 1115 Pharmacology and Pharmaceutical Sciences, 1701 Psychology, 1702 Cognitive Sciences
dc.subject.classification	Behavioral Science & Comparative Psychology
dc.subject.classification	Pharmacology & Pharmacy
dc.subject.classification	3109 Zoology
dc.subject.classification	3214 Pharmacology and pharmaceutical sciences
dc.subject.classification	5204 Cognitive and computational psychology
dc.subject.classification	5205 Social and personality psychology
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Urea
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Mitochondria
dc.subject.mesh	Apoptosis
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Membrane Potential, Mitochondrial
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Mitochondria
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Mice
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Urea
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Apoptosis
dc.subject.mesh	Membrane Potential, Mitochondrial
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Humans
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Fatty Acids
dc.subject.mesh	Urea
dc.subject.mesh	Reactive Oxygen Species
dc.subject.mesh	Mitochondria
dc.subject.mesh	Apoptosis
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Endoplasmic Reticulum Stress
dc.subject.mesh	Membrane Potential, Mitochondrial
dc.title	Inclusion of the in-chain sulfur in 3-thiaCTU increases the efficiency of mitochondrial targeting and cell killing by anticancer aryl-urea fatty acids.
dc.type	Journal Article
utslib.citation.volume	939
utslib.location.activity	Netherlands
utslib.for	0801 Artificial Intelligence and Image Processing
utslib.for	1115 Pharmacology and Pharmaceutical Sciences
utslib.for	1701 Psychology
utslib.for	1702 Cognitive Sciences
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Health
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access	*
dc.date.updated	2024-02-06T03:13:44Z
pubs.publication-status	Published
pubs.volume	939

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/175354