The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells
Date
2017
Authors
Vuckovic, S.
Vandyke, K.
Rickards, D.
McCauley Winter, P.
Brown, S.
Mitchell, T.
Liu, J.
Lu, J.
Askenase, P.
Yuriev, E.
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Journal article
Citation
British Journal of Haematology, 2017; 177(3):423-440
Statement of Responsibility
Slavica Vuckovic, Kate Vandyke, David A. Rickards, Padraig McCauley Winter, Simon H. J. Brown, Todd W. Mitchell, Jun Liu, Jun Lu, Philip W. Askenase, Elizabeth Yuriev, Ben Capuano, Paul A. Ramsland, Geoffrey R. Hill, Andrew C. W. Zannettino and Andrew T. Hutchinson
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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.
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© 2017 John Wiley & Sons Ltd.