Title

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

RIS ID

112645

Publication Details

Vuckovic, S., Vandyke, K., Rickards, D. A., McCauley Winter, P., Brown, S. H. J ., Mitchell, T. W., Liu, J., Lu, J., Askenase, P. W., Yuriev, E., Capuano, B., Ramsland, P. A., Hill, G. R., Zannettino, A. C. W. & Hutchinson, A. T. (2017). The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. British Journal of Haematology, 177 423-440.

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.

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Link to publisher version (DOI)

http://dx.doi.org/10.1111/bjh.14561