BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

Rath, EM; Cheng, YY; Pinese, M; Sarun, KH; Hudson, AL; Weir, C; Wang, YD; Håkansson, AP; Howell, VM; Liu, GJ; Reid, G; Knott, RB; Duff, AP; Bret Church, W

BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state

Rath, EM

Cheng, YY Pinese, M Sarun, KH

Hudson, AL Weir, C Wang, YD Håkansson, AP Howell, VM Liu, GJ Reid, G Knott, RB Duff, AP Bret Church, W

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Publication Type:: Journal Article
Citation:: PLoS ONE, 2018, 13 (8)
Issue Date:: 2018-08-01

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Field	Value	Language
dc.contributor.author	Rath, EM https://orcid.org/0000-0002-8430-5236	en_US
dc.contributor.author	Cheng, YY	en_US
dc.contributor.author	Pinese, M	en_US
dc.contributor.author	Sarun, KH https://orcid.org/0000-0003-4592-0671	en_US
dc.contributor.author	Hudson, AL	en_US
dc.contributor.author	Weir, C	en_US
dc.contributor.author	Wang, YD	en_US
dc.contributor.author	Håkansson, AP	en_US
dc.contributor.author	Howell, VM	en_US
dc.contributor.author	Liu, GJ	en_US
dc.contributor.author	Reid, G	en_US
dc.contributor.author	Knott, RB	en_US
dc.contributor.author	Duff, AP	en_US
dc.contributor.author	Bret Church, W	en_US
dc.date.available	2018-08-13	en_US
dc.date.issued	2018-08-01	en_US
dc.identifier.citation	PLoS ONE, 2018, 13 (8)	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128386
dc.description.abstract	© 2018 Rath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.	en_US
dc.relation.ispartof	PLoS ONE	en_US
dc.relation.isbasedon	10.1371/journal.pone.0203003	en_US
dc.subject.classification	General Science & Technology	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Cell Membrane	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mesothelioma	en_US
dc.subject.mesh	Lung Neoplasms	en_US
dc.subject.mesh	Mitochondrial Proton-Translocating ATPases	en_US
dc.subject.mesh	Oleic Acid	en_US
dc.subject.mesh	Lactalbumin	en_US
dc.subject.mesh	Antineoplastic Agents	en_US
dc.subject.mesh	Cell Survival	en_US
dc.subject.mesh	Molecular Conformation	en_US
dc.subject.mesh	Drug Resistance, Neoplasm	en_US
dc.subject.mesh	Hydrogen-Ion Concentration	en_US
dc.subject.mesh	Models, Molecular	en_US
dc.title	BAMLET kills chemotherapy-resistant mesothelioma cells, holding oleic acid in an activated cytotoxic state	en_US
dc.type	Journal Article
utslib.citation.volume	8	en_US
utslib.citation.volume	13	en_US
utslib.for	1112 Oncology and Carcinogenesis	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Students
utslib.copyright.status	closed_access
pubs.issue	8	en_US
pubs.publication-status	Published	en_US
pubs.volume	13	en_US

Abstract:

© 2018 Rath et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Malignant pleural mesothelioma is an aggressive cancer with poor prognosis. Here we have investigated in vitro efficacy of BAMLET and BLAGLET complexes (anti-cancer complexes consisting of oleic acid and bovine α-lactalbumin or β-lactoglobulin respectively) in killing mesothelioma cells, determined BAMLET and BLAGLET structures, and investigated possible biological mechanisms. We performed cell viability assays on 16 mesothelioma cell lines. BAMLET and BLAGLET having increasing oleic acid content inhibited human and rat mesothelioma cell line proliferation at decreasing doses. Most of the non-cancer primary human fibroblasts were more resistant to BAMLET than were human mesothelioma cells. BAMLET showed similar cytotoxicity to cisplatin-resistant, pemetrexed-resistant, vinorelbine-resistant, and parental rat mesothelioma cells, indicating the BAMLET anti-cancer mechanism may be different to drugs currently used to treat mesothelioma. Cisplatin, pemetrexed, gemcitabine, vinorelbine, and BAMLET, did not demonstrate a therapeutic window for mesothelioma compared with immortalised non-cancer mesothelial cells. We demonstrated by quantitative PCR that ATP synthase is downregulated in mesothelioma cells in response to regular dosing with BAMLET. We sought structural insight for BAMLET and BLAGLET activity by performing small angle X-ray scattering, circular dichroism, and scanning electron microscopy. Our results indicate the structural mechanism by which BAMLET and BLAGLET achieve increased cytotoxicity by holding increasing amounts of oleic acid in an active cytotoxic state encapsulated in increasingly unfolded protein. Our structural studies revealed similarity in the molecular structure of the protein components of these two complexes and in their encapsulation of the fatty acid, and differences in the microscopic structure and structural stability. BAMLET forms rounded aggregates and BLAGLET forms long fibre-like aggregates whose aggregation is more stable than that of BAMLET due to intermolecular disulphide bonds. The results reported here indicate that BAMLET and BLAGLET may be effective second-line treatment options for mesothelioma.

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http://hdl.handle.net/10453/128386