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|Title:||The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells|
|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|
|Citation:||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.|
|Appears in Collections:||Journal articles|
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