Reversal of glucocorticoid resistance in paediatric acute lymphoblastic leukaemia is dependent on restoring BIM expression.

Toscan, CE; Jing, D; Mayoh, C; Lock, RB

Reversal of glucocorticoid resistance in paediatric acute lymphoblastic leukaemia is dependent on restoring BIM expression.

Toscan, CE Jing, D

Mayoh, C Lock, RB

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Publisher:: NATURE PUBLISHING GROUP
Publication Type:: Journal Article
Citation:: British journal of cancer, 2020, 122, (12), pp. 1769-1781
Issue Date:: 2020-06

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Field	Value	Language
dc.contributor.author	Toscan, CE
dc.contributor.author	Jing, D https://orcid.org/0000-0002-1491-8002
dc.contributor.author	Mayoh, C
dc.contributor.author	Lock, RB
dc.date.accessioned	2021-04-16T04:31:21Z
dc.date.available	2020-03-09
dc.date.available	2021-04-16T04:31:21Z
dc.date.issued	2020-06
dc.identifier.citation	British journal of cancer, 2020, 122, (12), pp. 1769-1781
dc.identifier.issn	0007-0920
dc.identifier.issn	1532-1827
dc.identifier.uri	http://hdl.handle.net/10453/148169
dc.description.abstract	<h4>Background</h4>Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Glucocorticoids form a critical component of chemotherapy regimens and resistance to glucocorticoid therapy is predictive of poor outcome. We have previously shown that glucocorticoid resistance is associated with upregulation of the oncogene C-MYC and failure to induce the proapoptotic gene BIM.<h4>Methods</h4>A high-throughput screening (HTS) campaign was carried out to identify glucocorticoid sensitisers against an ALL xenograft derived from a glucocorticoid-resistant paediatric patient. Gene expression analysis was carried out using Illumina microarrays. Efficacy, messenger RNA and protein analysis were carried out by Resazurin assay, reverse transcription-PCR and immunoblotting, respectively.<h4>Results</h4>A novel glucocorticoid sensitiser, 2-((4,5-dihydro-1H-imidazol-2-yl)thio)-N-isopropyl-N-phenylacetamide (GCS-3), was identified from the HTS campaign. The sensitising effect was specific to glucocorticoids and synergy was observed in a range of dexamethasone-resistant and dexamethasone-sensitive xenografts representative of B-ALL, T-ALL and Philadelphia chromosome-positive ALL. GCS-3 in combination with dexamethasone downregulated C-MYC and significantly upregulated BIM expression in a glucocorticoid-resistant ALL xenograft. The GCS-3/dexamethasone combination significantly increased binding of the glucocorticoid receptor to a novel BIM enhancer, which is associated with glucocorticoid sensitivity.<h4>Conclusions</h4>This study describes the potential of the novel glucocorticoid sensitiser, GCS-3, as a biological tool to interrogate glucocorticoid action and resistance.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	NATURE PUBLISHING GROUP
dc.relation.ispartof	British journal of cancer
dc.relation.isbasedon	10.1038/s41416-020-0824-8
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.subject	1112 Oncology and Carcinogenesis, 1117 Public Health and Health Services
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Animals
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Bcl-2-Like Protein 11
dc.subject.mesh	Dexamethasone
dc.subject.mesh	Drug Discovery
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Humans
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Receptors, Glucocorticoid
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Animals
dc.subject.mesh	Humans
dc.subject.mesh	Dexamethasone
dc.subject.mesh	Receptors, Glucocorticoid
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Drug Discovery
dc.subject.mesh	Bcl-2-Like Protein 11
dc.subject.mesh	Animals
dc.subject.mesh	Antineoplastic Agents
dc.subject.mesh	Bcl-2-Like Protein 11
dc.subject.mesh	Dexamethasone
dc.subject.mesh	Drug Discovery
dc.subject.mesh	Drug Resistance, Neoplasm
dc.subject.mesh	Glucocorticoids
dc.subject.mesh	Humans
dc.subject.mesh	Precursor Cell Lymphoblastic Leukemia-Lymphoma
dc.subject.mesh	Receptors, Glucocorticoid
dc.subject.mesh	Xenograft Model Antitumor Assays
dc.title	Reversal of glucocorticoid resistance in paediatric acute lymphoblastic leukaemia is dependent on restoring BIM expression.
dc.type	Journal Article
utslib.citation.volume	122
utslib.location.activity	England
utslib.for	1112 Oncology and Carcinogenesis
utslib.for	1117 Public Health and Health Services
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 Engineering and Information Technology/School of Biomedical Engineering
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
utslib.copyright.embargo	2022-04-19T00:00:00+1000Z
dc.date.updated	2021-04-16T04:31:17Z
pubs.issue	12
pubs.publication-status	Published
pubs.volume	122
utslib.citation.issue	12

Abstract:

Background

Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Glucocorticoids form a critical component of chemotherapy regimens and resistance to glucocorticoid therapy is predictive of poor outcome. We have previously shown that glucocorticoid resistance is associated with upregulation of the oncogene C-MYC and failure to induce the proapoptotic gene BIM.

Methods

A high-throughput screening (HTS) campaign was carried out to identify glucocorticoid sensitisers against an ALL xenograft derived from a glucocorticoid-resistant paediatric patient. Gene expression analysis was carried out using Illumina microarrays. Efficacy, messenger RNA and protein analysis were carried out by Resazurin assay, reverse transcription-PCR and immunoblotting, respectively.

Results

A novel glucocorticoid sensitiser, 2-((4,5-dihydro-1H-imidazol-2-yl)thio)-N-isopropyl-N-phenylacetamide (GCS-3), was identified from the HTS campaign. The sensitising effect was specific to glucocorticoids and synergy was observed in a range of dexamethasone-resistant and dexamethasone-sensitive xenografts representative of B-ALL, T-ALL and Philadelphia chromosome-positive ALL. GCS-3 in combination with dexamethasone downregulated C-MYC and significantly upregulated BIM expression in a glucocorticoid-resistant ALL xenograft. The GCS-3/dexamethasone combination significantly increased binding of the glucocorticoid receptor to a novel BIM enhancer, which is associated with glucocorticoid sensitivity.

Conclusions

This study describes the potential of the novel glucocorticoid sensitiser, GCS-3, as a biological tool to interrogate glucocorticoid action and resistance.

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

http://hdl.handle.net/10453/148169