The Novel Anticancer Aryl-Ureido Fatty Acid CTU Increases Reactive Oxygen Species Production That Impairs Mitochondrial Fusion Mechanisms and Promotes MDA-MB-231 Cell Death.
- Publisher:
- MDPI
- Publication Type:
- Journal Article
- Citation:
- Int J Mol Sci, 2024, 25, (19), pp. 10577
- Issue Date:
- 2024-10-01
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Field | Value | Language |
---|---|---|
dc.contributor.author | Tam, S | |
dc.contributor.author | Umashankar, B | |
dc.contributor.author | Rahman, MK | |
dc.contributor.author | Choucair, H | |
dc.contributor.author |
Rawling, T https://orcid.org/0000-0002-6624-6586 |
|
dc.contributor.author | Murray, M | |
dc.date.accessioned | 2024-12-02T01:05:35Z | |
dc.date.available | 2024-09-28 | |
dc.date.available | 2024-12-02T01:05:35Z | |
dc.date.issued | 2024-10-01 | |
dc.identifier.citation | Int J Mol Sci, 2024, 25, (19), pp. 10577 | |
dc.identifier.issn | 1422-0067 | |
dc.identifier.issn | 1422-0067 | |
dc.identifier.uri | http://hdl.handle.net/10453/182203 | |
dc.description.abstract | Cancer cell mitochondria are functionally different from those in normal cells and could be targeted to develop novel anticancer agents. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of targeted agents that enhance the production of reactive oxygen species (ROS) that disrupt the outer mitochondrial membrane (OMM) and kill cancer cells. However, the mechanism by which CTU disrupts the inner mitochondrial membrane (IMM) and activates apoptosis is not clear. Here, we show that CTU-mediated ROS selectively dysregulated the OMA1/OPA1 fusion regulatory system located in the IMM. The essential role of ROS was confirmed in experiments with the lipid peroxyl scavenger α-tocopherol, which prevented the dysregulation of OMA1/OPA1 and CTU-mediated MDA-MB-231 cell killing. The disruption of OMA1/OPA1 and IMM fusion by CTU-mediated ROS accounted for the release of cytochrome c from the mitochondria and the activation of apoptosis. Taken together, these findings demonstrate that CTU depolarises the mitochondrial membrane, activates ROS production, and disrupts both the IMM and OMM, which releases cytochrome c and activates apoptosis. Mitochondrial-targeting agents like CTU offer a novel approach to the development of new therapeutics with anticancer activity. | |
dc.format | Electronic | |
dc.language | eng | |
dc.publisher | MDPI | |
dc.relation.ispartof | Int J Mol Sci | |
dc.relation.isbasedon | 10.3390/ijms251910577 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject | 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences | |
dc.subject.classification | Chemical Physics | |
dc.subject.classification | 3101 Biochemistry and cell biology | |
dc.subject.classification | 3107 Microbiology | |
dc.subject.classification | 3404 Medicinal and biomolecular chemistry | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Reactive Oxygen Species | |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Mitochondrial Dynamics | |
dc.subject.mesh | Mitochondria | |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Fatty Acids | |
dc.subject.mesh | Membrane Potential, Mitochondrial | |
dc.subject.mesh | Mitochondrial Membranes | |
dc.subject.mesh | Cytochromes c | |
dc.subject.mesh | Breast Neoplasms | |
dc.subject.mesh | MDA-MB-231 Cells | |
dc.subject.mesh | Cell Line, Tumor | |
dc.subject.mesh | Mitochondria | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Breast Neoplasms | |
dc.subject.mesh | Reactive Oxygen Species | |
dc.subject.mesh | Cytochromes c | |
dc.subject.mesh | Fatty Acids | |
dc.subject.mesh | Antineoplastic Agents | |
dc.subject.mesh | Apoptosis | |
dc.subject.mesh | Mitochondrial Membranes | |
dc.subject.mesh | Membrane Potential, Mitochondrial | |
dc.subject.mesh | Mitochondrial Dynamics | |
dc.subject.mesh | MDA-MB-231 Cells | |
dc.title | The Novel Anticancer Aryl-Ureido Fatty Acid CTU Increases Reactive Oxygen Species Production That Impairs Mitochondrial Fusion Mechanisms and Promotes MDA-MB-231 Cell Death. | |
dc.type | Journal Article | |
utslib.citation.volume | 25 | |
utslib.location.activity | Switzerland | |
utslib.for | 0399 Other Chemical Sciences | |
utslib.for | 0604 Genetics | |
utslib.for | 0699 Other Biological Sciences | |
pubs.organisational-group | University of Technology Sydney | |
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 | open_access | * |
dc.rights.license | This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ | |
dc.date.updated | 2024-12-02T01:05:31Z | |
pubs.issue | 19 | |
pubs.publication-status | Published online | |
pubs.volume | 25 | |
utslib.citation.issue | 19 |
Abstract:
Cancer cell mitochondria are functionally different from those in normal cells and could be targeted to develop novel anticancer agents. The aryl-ureido fatty acid CTU (16({[4-chloro-3-(trifluoromethyl)phenyl]-carbamoyl}amino)hexadecanoic acid) is the prototype of a new class of targeted agents that enhance the production of reactive oxygen species (ROS) that disrupt the outer mitochondrial membrane (OMM) and kill cancer cells. However, the mechanism by which CTU disrupts the inner mitochondrial membrane (IMM) and activates apoptosis is not clear. Here, we show that CTU-mediated ROS selectively dysregulated the OMA1/OPA1 fusion regulatory system located in the IMM. The essential role of ROS was confirmed in experiments with the lipid peroxyl scavenger α-tocopherol, which prevented the dysregulation of OMA1/OPA1 and CTU-mediated MDA-MB-231 cell killing. The disruption of OMA1/OPA1 and IMM fusion by CTU-mediated ROS accounted for the release of cytochrome c from the mitochondria and the activation of apoptosis. Taken together, these findings demonstrate that CTU depolarises the mitochondrial membrane, activates ROS production, and disrupts both the IMM and OMM, which releases cytochrome c and activates apoptosis. Mitochondrial-targeting agents like CTU offer a novel approach to the development of new therapeutics with anticancer activity.
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