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

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 Ramsland, Geoffrey R. Hill, Andrew C W Zannettino, Andrew T. Hutchinson

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10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)423-440
Number of pages18
JournalBritish Journal of Haematology
Volume177
Issue number3
DOIs
Publication statusPublished - May 2017

Keywords

  • GW4869
  • Multiple myeloma
  • Phosphatidylserine
  • Small molecule

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