title: The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells.
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.
authors.affiliation: The Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.|School of Medicine, University of Queensland, Brisbane, Qld, Australia.|Mater Research, Translational Research Institute, Brisbane, Qld, Australia.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.affiliation: Faculty of Health and Medical Sciences, SA Pathology, The University of Adelaide, Adelaide, SA.|Cancer Theme, South Australian Health and Medical Research Institute, SA Pathology, Adelaide, SA, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Vandyke
authors.affiliation: School of Life Sciences, Centre for Health Technologies and the iThree Institute, University of Technology Sydney, Ultimo, NSW, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Rickards
authors.affiliation: School of Life Sciences, Centre for Health Technologies and the iThree Institute, University of Technology Sydney, Ultimo, NSW, Australia.
authors.forename: Padraig
authors.initials: P
authors.lastname: McCauley Winter
authors.affiliation: School of Biology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Simon H J
authors.initials: SHJ
authors.lastname: Brown
authors.affiliation: School of Biology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Mitchell
authors.affiliation: Department of Genetics, Yale Stem Cell Center, Yale Cancer Center and Yale Center for RNA Science and Medicine, New Haven, CT, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Genetics, Yale Stem Cell Center, Yale Cancer Center and Yale Center for RNA Science and Medicine, New Haven, CT, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Section of Allergy and Clinical Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Askenase
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Yuriev
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
authors.forename: Ben
authors.initials: B
authors.lastname: Capuano
authors.affiliation: School of Science, RMIT University, Bundoora, VIC, Australia.|Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.|Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, VIC, Australia.|Department of Surgery Austin Health, University of Melbourne, Heidelberg, Vic, Australia.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
authors.affiliation: The Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.|Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Herston, Qld, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Faculty of Health and Medical Sciences, SA Pathology, The University of Adelaide, Adelaide, SA.|Cancer Theme, South Australian Health and Medical Research Institute, SA Pathology, Adelaide, SA, Australia.
authors.forename: Andrew C W
authors.initials: ACW
authors.lastname: Zannettino
authors.affiliation: School of Life Sciences, Centre for Health Technologies and the iThree Institute, University of Technology Sydney, Ultimo, NSW, Australia.|Section of Allergy and Clinical Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.|Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.
authors.forename: Andrew T
authors.identifier: 0000-0003-2535-3729
authors.initials: AT
authors.lastname: Hutchinson
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001597:Benzylidene Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010718:Phosphatidylserines / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; C468773:GW 4869; D010718:Phosphatidylserines
keywords: GW4869; multiple myeloma; phosphatidylserine; small molecule