The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells

Vuckovic, S; Vandyke, K; Rickards, DA; McCauley Winter, P; Brown, SHJ; Mitchell, TW; Liu, J; Lu, J; Askenase, PW; Yuriev, E; Capuano, B; Ramsland, PA; Hill, GR; Zannettino, ACW; Hutchinson, AT

The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells

Vuckovic, S Vandyke, K Rickards, DA McCauley Winter, P Brown, SHJ Mitchell, TW Liu, J Lu, J Askenase, PW Yuriev, E Capuano, B Ramsland, PA Hill, GR Zannettino, ACW Hutchinson, AT

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Publication Type:: Journal Article
Citation:: British Journal of Haematology, 2017, 177 (3), pp. 423 - 440
Issue Date:: 2017-05-01

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Field	Value	Language
dc.contributor.author	Vuckovic, S	en_US
dc.contributor.author	Vandyke, K	en_US
dc.contributor.author	Rickards, DA	en_US
dc.contributor.author	McCauley Winter, P	en_US
dc.contributor.author	Brown, SHJ	en_US
dc.contributor.author	Mitchell, TW	en_US
dc.contributor.author	Liu, J	en_US
dc.contributor.author	Lu, J	en_US
dc.contributor.author	Askenase, PW	en_US
dc.contributor.author	Yuriev, E	en_US
dc.contributor.author	Capuano, B	en_US
dc.contributor.author	Ramsland, PA	en_US
dc.contributor.author	Hill, GR	en_US
dc.contributor.author	Zannettino, ACW	en_US
dc.contributor.author	Hutchinson, AT https://orcid.org/0000-0003-2535-3729	en_US
dc.date.available	2016-12-01	en_US
dc.date.issued	2017-05-01	en_US
dc.identifier.citation	British Journal of Haematology, 2017, 177 (3), pp. 423 - 440	en_US
dc.identifier.issn	0007-1048	en_US
dc.identifier.uri	http://hdl.handle.net/10453/126961
dc.description.abstract	© 2017 John Wiley & Sons Ltd We have discovered that a small cationic molecule, GW4869, is cytotoxic to a subset of myeloma cell lines and primary myeloma plasma cells. Biochemical analysis revealed that GW4869 binds to anionic phospholipids such as phosphatidylserine - a lipid normally confined to the intracellular side of the cell membrane. However, interestingly, phosphatidylserine was expressed on the surface of all myeloma cell lines tested (n = 12) and 9/15 primary myeloma samples. Notably, the level of phosphatidylserine expression correlated well with sensitivity to GW4869. Inhibition of cell surface phosphatidylserine exposure with brefeldin A resulted in resistance to GW4869. Finally, GW4869 was shown to delay the growth of phosphatidylserine-high myeloma cells in vivo. To the best of our knowledge, this is the first example of using a small molecule to target phosphatidylserine on malignant cells. This study may provide the rationale for the development of phosphatidylserine-targeting small molecules for the treatment of surface phosphatidylserine-expressing cancers.	en_US
dc.relation.ispartof	British Journal of Haematology	en_US
dc.relation.isbasedon	10.1111/bjh.14561	en_US
dc.subject.classification	Immunology	en_US
dc.subject.mesh	Cell Line, Tumor	en_US
dc.subject.mesh	Tumor Cells, Cultured	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Mice, SCID	en_US
dc.subject.mesh	Multiple Myeloma	en_US
dc.subject.mesh	Aniline Compounds	en_US
dc.subject.mesh	Benzylidene Compounds	en_US
dc.subject.mesh	Phosphatidylserines	en_US
dc.subject.mesh	Antineoplastic Agents	en_US
dc.subject.mesh	Xenograft Model Antitumor Assays	en_US
dc.subject.mesh	Cell Death	en_US
dc.subject.mesh	Dose-Response Relationship, Drug	en_US
dc.title	The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	177	en_US
utslib.for	1102 Cardiorespiratory Medicine and Haematology	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/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Medical and Molecular Sciences
utslib.copyright.status	closed_access
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	177	en_US

Abstract:

© 2017 John Wiley & Sons Ltd We have discovered that a small cationic molecule, GW4869, is cytotoxic to a subset of myeloma cell lines and primary myeloma plasma cells. Biochemical analysis revealed that GW4869 binds to anionic phospholipids such as phosphatidylserine - a lipid normally confined to the intracellular side of the cell membrane. However, interestingly, phosphatidylserine was expressed on the surface of all myeloma cell lines tested (n = 12) and 9/15 primary myeloma samples. Notably, the level of phosphatidylserine expression correlated well with sensitivity to GW4869. Inhibition of cell surface phosphatidylserine exposure with brefeldin A resulted in resistance to GW4869. Finally, GW4869 was shown to delay the growth of phosphatidylserine-high myeloma cells in vivo. To the best of our knowledge, this is the first example of using a small molecule to target phosphatidylserine on malignant cells. This study may provide the rationale for the development of phosphatidylserine-targeting small molecules for the treatment of surface phosphatidylserine-expressing cancers.

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http://hdl.handle.net/10453/126961