Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.

Seneviratne, JA; Carter, DR; Mittra, R; Gifford, A; Kim, PY; Luo, J-S; Mayoh, C; Salib, A; Rahmanto, AS; Murray, J; Cheng, NC; Nagy, Z; Wang, Q; Kleynhans, A; Tan, O; Sutton, SK; Xue, C; Chung, SA; Zhang, Y; Sun, C; Zhang, L; Haber, M; Norris, MD; Fletcher, JI; Liu, T; Dilda, PJ; Hogg, PJ; Cheung, BB; Marshall, GM

Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.

Seneviratne, JA Carter, DR Mittra, R Gifford, A Kim, PY Luo, J-S Mayoh, C Salib, A Rahmanto, AS Murray, J Cheng, NC Nagy, Z Wang, Q Kleynhans, A Tan, O Sutton, SK Xue, C Chung, SA Zhang, Y Sun, C Zhang, L Haber, M Norris, MD Fletcher, JI Liu, T Dilda, PJ Hogg, PJ Cheung, BB Marshall, GM

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Publisher:: Wiley
Publication Type:: Journal Article
Citation:: International Journal of Cancer, 2023, 152, (7), pp. 1399-1413
Issue Date:: 2023-04-01

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Field	Value	Language
dc.contributor.author	Seneviratne, JA
dc.contributor.author	Carter, DR
dc.contributor.author	Mittra, R
dc.contributor.author	Gifford, A
dc.contributor.author	Kim, PY
dc.contributor.author	Luo, J-S
dc.contributor.author	Mayoh, C
dc.contributor.author	Salib, A
dc.contributor.author	Rahmanto, AS
dc.contributor.author	Murray, J
dc.contributor.author	Cheng, NC
dc.contributor.author	Nagy, Z
dc.contributor.author	Wang, Q
dc.contributor.author	Kleynhans, A
dc.contributor.author	Tan, O
dc.contributor.author	Sutton, SK
dc.contributor.author	Xue, C
dc.contributor.author	Chung, SA
dc.contributor.author	Zhang, Y
dc.contributor.author	Sun, C
dc.contributor.author	Zhang, L
dc.contributor.author	Haber, M
dc.contributor.author	Norris, MD
dc.contributor.author	Fletcher, JI
dc.contributor.author	Liu, T
dc.contributor.author	Dilda, PJ
dc.contributor.author	Hogg, PJ
dc.contributor.author	Cheung, BB
dc.contributor.author	Marshall, GM
dc.date.accessioned	2024-04-29T01:31:01Z
dc.date.available	2022-09-26
dc.date.available	2024-04-29T01:31:01Z
dc.date.issued	2023-04-01
dc.identifier.citation	International Journal of Cancer, 2023, 152, (7), pp. 1399-1413
dc.identifier.issn	0020-7136
dc.identifier.issn	1097-0215
dc.identifier.uri	http://hdl.handle.net/10453/178437
dc.description.abstract	The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Wiley
dc.relation.ispartof	International Journal of Cancer
dc.relation.isbasedon	10.1002/ijc.34349
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Adenine Nucleotide Translocator 2
dc.subject.mesh	Animals
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Apoptosis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Histones
dc.subject.mesh	Hydroxamic Acids
dc.subject.mesh	Mice
dc.subject.mesh	Mitochondria
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Vorinostat
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Apoptosis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Histones
dc.subject.mesh	Hydroxamic Acids
dc.subject.mesh	Mitochondria
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Vorinostat
dc.subject.mesh	Adenine Nucleotide Translocator 2
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Mitochondria
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Hydroxamic Acids
dc.subject.mesh	Adenine Nucleotide Translocator 2
dc.subject.mesh	Histones
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Apoptosis
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Vorinostat
dc.subject.mesh	Animals
dc.subject.mesh	Mice
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Apoptosis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Histones
dc.subject.mesh	Hydroxamic Acids
dc.subject.mesh	Mitochondria
dc.subject.mesh	Neuroblastoma
dc.subject.mesh	Vorinostat
dc.subject.mesh	Adenine Nucleotide Translocator 2
dc.title	Inhibition of mitochondrial translocase SLC25A5 and histone deacetylation is an effective combination therapy in neuroblastoma.
dc.type	Journal Article
utslib.citation.volume	152
utslib.location.activity	United States
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	University of Technology Sydney
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	University of Technology Sydney/Faculty of Science
pubs.organisational-group	University of Technology Sydney/Strength - CHT - Health Technologies
pubs.organisational-group	University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2024-04-29T01:30:59Z
pubs.issue	7
pubs.publication-status	Published
pubs.volume	152
utslib.citation.issue	7

Abstract:

The mitochondrion is a gatekeeper of apoptotic processes, and mediates drug resistance to several chemotherapy agents used to treat cancer. Neuroblastoma is a common solid cancer in young children with poor clinical outcomes following conventional chemotherapy. We sought druggable mitochondrial protein targets in neuroblastoma cells. Among mitochondria-associated gene targets, we found that high expression of the mitochondrial adenine nucleotide translocase 2 (SLC25A5/ANT2), was a strong predictor of poor neuroblastoma patient prognosis and contributed to a more malignant phenotype in pre-clinical models. Inhibiting this transporter with PENAO reduced cell viability in a panel of neuroblastoma cell lines in a TP53-status-dependant manner. We identified the histone deacetylase inhibitor, suberanilohydroxamic acid (SAHA), as the most effective drug in clinical use against mutant TP53 neuroblastoma cells. SAHA and PENAO synergistically reduced cell viability, and induced apoptosis, in neuroblastoma cells independent of TP53-status. The SAHA and PENAO drug combination significantly delayed tumour progression in pre-clinical neuroblastoma mouse models, suggesting that these clinically advanced inhibitors may be effective in treating the disease.

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http://hdl.handle.net/10453/178437