1. The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells
- Author
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Vuckovic, S, Vandyke, K, Rickards, DA, McCauley Winter, P, Brown, SHJ, Mitchell, TW, Liu, J, Lu, J, Askenase, PW, Yuriev, E, Capuano, B, Ramsland, PA, Hill, GR, Zannettino, ACW, and Hutchinson, AT
- Subjects
Aniline Compounds ,Cell Death ,Dose-Response Relationship, Drug ,Immunology ,Antineoplastic Agents ,Mice, SCID ,Phosphatidylserines ,Benzylidene Compounds ,Xenograft Model Antitumor Assays ,Cell Line, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Multiple Myeloma - Abstract
© 2017 John Wiley & Sons Ltd 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.
- Published
- 2016