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

2017-05

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

GW4869

Multiple myeloma

Phosphatidylserine

Small molecule

Journal Article

10.1111/bjh.14561

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.

link

British Journal of Haematology 2017; 177(3): 423-440

British Journal of Haematology