Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/16735
Title: The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells
Austin Authors: Vuckovic, Slavica;Vandyke, Kate;Rickards, David A;McCauley Winter, Padraig;Brown, Simon HJ;Mitchell, Todd W;Liu, Jun;Lu, Jun;Askenase, Philip W;Yuriev, Elizabeth;Capuano, Ben;Ramsland, Paul A ;Hill, Geoffrey R;Zannettino, Andrew CW;Hutchinson, Andrew T
Affiliation: The Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
School of Medicine, University of Queensland, Brisbane, Queensland, Australia
Mater Research, Translational Research Institute, Brisbane, Queensland, Australia
Faculty of Health and Medical Sciences, SA Pathology, The University of Adelaide, Adelaide, SA, Australia
Cancer Theme, South Australian Health and Medical Research Institute, SA Pathology, Adelaide, SA, Australia
School of Life Sciences, Centre for Health Technologies and the iThree Institute, University of Technology Sydney, Ultimo, NSW, Australia
School of Biology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
Department of Genetics, Yale Stem Cell Center, Yale Cancer Center and Yale Center for RNA Science and Medicine, New Haven, CT, USA
Section of Allergy and Clinical Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
School of Science, RMIT University, Bundoora, Victoria, Australia
Centre for Biomedical Research, Burnet Institute, Melbourne, Victoria, Australia
Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia
Department of Surgery Austin Health, University of Melbourne, Victoria, Australia
Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Herston, , Queensland, Australia
Issue Date: May-2017
metadata.dc.date: 2017-02-17
Publication information: British Journal of Haematology 2017; 177(3): 423-440
Abstract: 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/16735
DOI: 10.1111/bjh.14561
PubMed URL: https://pubmed.ncbi.nlm.nih.gov/28211573
Type: Journal Article
Subjects: GW4869
Multiple myeloma
Phosphatidylserine
Small molecule
Appears in Collections:Journal articles

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