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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 | 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: | https://ahro.austin.org.au/austinjspui/handle/1/16735 | DOI: | 10.1111/bjh.14561 | Journal: | British Journal of Haematology | 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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