Format

Send to

Choose Destination
See comment in PubMed Commons below
Br J Haematol. 2017 Feb 17. doi: 10.1111/bjh.14561. [Epub ahead of print]

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

Author information

1
The Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.
2
School of Medicine, University of Queensland, Brisbane, Qld, Australia.
3
Mater Research, Translational Research Institute, Brisbane, Qld, Australia.
4
Faculty of Health and Medical Sciences, SA Pathology, The University of Adelaide, Adelaide, SA.
5
Cancer Theme, South Australian Health and Medical Research Institute, SA Pathology, Adelaide, SA, Australia.
6
School of Life Sciences, Centre for Health Technologies and the iThree Institute, University of Technology Sydney, Ultimo, NSW, Australia.
7
School of Biology and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
8
Department of Genetics, Yale Stem Cell Center, Yale Cancer Center and Yale Center for RNA Science and Medicine, New Haven, CT, USA.
9
Section of Allergy and Clinical Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
10
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.
11
School of Science, RMIT University, Bundoora, VIC, Australia.
12
Centre for Biomedical Research, Burnet Institute, Melbourne, VIC, Australia.
13
Department of Immunology, Monash University, Alfred Medical Research and Education Precinct, Melbourne, VIC, Australia.
14
Department of Surgery Austin Health, University of Melbourne, Heidelberg, Vic, Australia.
15
Department of Bone Marrow Transplantation, The Royal Brisbane and Women's Hospital, Herston, Qld, Australia.

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.

KEYWORDS:

GW4869; multiple myeloma; phosphatidylserine; small molecule

PMID:
28211573
DOI:
10.1111/bjh.14561
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Wiley
    Loading ...
    Support Center