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

Journal Article


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.

UOW Authors


  •   Vuckovic, Slavica (external author)
  •   Vandyke, Kate (external author)
  •   Rickards, David (external author)
  •   Mccauley, Padraig (external author)
  •   Brown, Simon (external author)
  •   Mitchell, Todd
  •   Liu, Jun (external author)
  •   Lu, Jun (external author)
  •   Askenase, Philip (external author)
  •   Yuriev, Elizabeth (external author)
  •   Capuano, Ben (external author)
  •   Ramsland, Paul (external author)
  •   Hill, Geoffrey R. (external author)
  •   Zannettino, Andrew (external author)
  •   Hutchinson, Andrew (external author)

Publication Date


  • 2017

Citation


  • 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.

Scopus Eid


  • 2-s2.0-85013354708

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1063

Number Of Pages


  • 17

Start Page


  • 423

End Page


  • 440

Volume


  • 177

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.

UOW Authors


  •   Vuckovic, Slavica (external author)
  •   Vandyke, Kate (external author)
  •   Rickards, David (external author)
  •   Mccauley, Padraig (external author)
  •   Brown, Simon (external author)
  •   Mitchell, Todd
  •   Liu, Jun (external author)
  •   Lu, Jun (external author)
  •   Askenase, Philip (external author)
  •   Yuriev, Elizabeth (external author)
  •   Capuano, Ben (external author)
  •   Ramsland, Paul (external author)
  •   Hill, Geoffrey R. (external author)
  •   Zannettino, Andrew (external author)
  •   Hutchinson, Andrew (external author)

Publication Date


  • 2017

Citation


  • 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.

Scopus Eid


  • 2-s2.0-85013354708

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1063

Number Of Pages


  • 17

Start Page


  • 423

End Page


  • 440

Volume


  • 177