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The cationic small molecule GW 4869 is cytotoxic to high phosphatidylserine‐expressing myeloma cells
Author(s) -
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.
Publication year - 2017
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.14561
Subject(s) - phosphatidylserine , cytotoxic t cell , biology , microbiology and biotechnology , chemistry , in vitro , biochemistry , membrane , phospholipid
Summary We have discovered that a small cationic molecule, GW 4869, is cytotoxic to a subset of myeloma cell lines and primary myeloma plasma cells. Biochemical analysis revealed that GW 4869 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 GW 4869. Inhibition of cell surface phosphatidylserine exposure with brefeldin A resulted in resistance to GW 4869. Finally, GW 4869 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.