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

Vuckovic, Slavica, Vandyke, Kate, Rickards, David A. , Mccauley Winter, Padraig, Brown, Simon H. J. , Mitchell, Todd W. , Liu, Jun, Lu, Jun, Askenase, Philip W. , Yuriev, Elizabeth, Capuano, Ben, Ramsland, Paul A. , Hill, Geoffrey R. , Zannettino, Andrew C. W. and Hutchinson, Andrew T. (2017) The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. British Journal of Haematology, . doi:10.1111/bjh.14561


Author Vuckovic, Slavica
Vandyke, Kate
Rickards, David A.
Mccauley Winter, Padraig
Brown, Simon H. J.
Mitchell, Todd W.
Liu, Jun
Lu, Jun
Askenase, Philip W.
Yuriev, Elizabeth
Capuano, Ben
Ramsland, Paul A.
Hill, Geoffrey R.
Zannettino, Andrew C. W.
Hutchinson, Andrew T.
Title The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells
Journal name British Journal of Haematology   Check publisher's open access policy
ISSN 1365-2141
0007-1048
Publication date 2017-02-17
Sub-type Article (original research)
DOI 10.1111/bjh.14561
Open Access Status Not yet assessed
Total pages 18
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Collection year 2018
Language eng
Formatted 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.
Keyword GW4869
Multiple myeloma
Phosphatidylserine
Small molecule
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Mater Research Institute-UQ (MRI-UQ)
HERDC Pre-Audit
School of Medicine Publications
 
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