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

Research output: Contribution to journalArticleResearchpeer-review

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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

Cite this

Vuckovic, S., Vandyke, K., Rickards, D. A., Mccauley Winter, P., Brown, S. H. J., Mitchell, T. W., ... Hutchinson, A. T. (2017). The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. British Journal of Haematology, 177(3), 423-440. https://doi.org/10.1111/bjh.14561
Vuckovic, Slavica ; Vandyke, Kate ; Rickards, David A. ; Mccauley Winter, Padraig ; Brown, Simon H J ; Mitchell, Todd W. ; Liu, Jun ; Lu, Jun ; Askenase, Philip W. ; Yuriev, Elizabeth ; Capuano, Ben ; Ramsland, Paul ; Hill, Geoffrey R. ; Zannettino, Andrew C W ; Hutchinson, Andrew T. / The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. In: British Journal of Haematology. 2017 ; Vol. 177, No. 3. pp. 423-440.
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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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author = "Slavica Vuckovic and Kate Vandyke and Rickards, {David A.} and {Mccauley Winter}, Padraig and Brown, {Simon H J} and Mitchell, {Todd W.} and Jun Liu and Jun Lu and Askenase, {Philip W.} and Elizabeth Yuriev and Ben Capuano and Paul Ramsland and Hill, {Geoffrey R.} and Zannettino, {Andrew C W} and Hutchinson, {Andrew T.}",
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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, P, Hill, GR, Zannettino, ACW & Hutchinson, AT 2017, 'The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells', British Journal of Haematology, vol. 177, no. 3, pp. 423-440. https://doi.org/10.1111/bjh.14561

The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. / Vuckovic, Slavica; Vandyke, Kate; Rickards, David A.; Mccauley Winter, Padraig; Brown, Simon H J; Mitchell, Todd W.; Liu, Jun; Lu, Jun; Askenase, Philip W.; Yuriev, Elizabeth; Capuano, Ben; Ramsland, Paul; Hill, Geoffrey R.; Zannettino, Andrew C W; Hutchinson, Andrew T.

In: British Journal of Haematology, Vol. 177, No. 3, 05.2017, p. 423-440.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells

AU - Vuckovic, Slavica

AU - Vandyke, Kate

AU - Rickards, David A.

AU - Mccauley Winter, Padraig

AU - Brown, Simon H J

AU - Mitchell, Todd W.

AU - Liu, Jun

AU - Lu, Jun

AU - Askenase, Philip W.

AU - Yuriev, Elizabeth

AU - Capuano, Ben

AU - Ramsland, Paul

AU - Hill, Geoffrey R.

AU - Zannettino, Andrew C W

AU - Hutchinson, Andrew T.

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N2 - 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.

AB - 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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JF - British Journal of Haematology

SN - 0007-1048

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Vuckovic S, Vandyke K, Rickards DA, Mccauley Winter P, Brown SHJ, Mitchell TW et al. The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells. British Journal of Haematology. 2017 May;177(3):423-440. https://doi.org/10.1111/bjh.14561