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 A, Hill Geoffrey R, Zannettino Andrew C W, Hutchinson Andrew T
The Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Qld, Australia.
School of Medicine, University of Queensland, Brisbane, Qld, Australia.
Br J Haematol. 2017 May;177(3):423-440. doi: 10.1111/bjh.14561. Epub 2017 Feb 17.
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.
我们发现一种小分子阳离子化合物GW4869对一部分骨髓瘤细胞系和原发性骨髓瘤浆细胞具有细胞毒性。生化分析表明，GW4869与阴离子磷脂如磷脂酰丝氨酸结合，磷脂酰丝氨酸是一种通常局限于细胞膜内侧的脂质。然而，有趣的是，在所检测的所有骨髓瘤细胞系（n = 12）和15份原发性骨髓瘤样本中的9份中，磷脂酰丝氨酸都表达于细胞表面。值得注意的是，磷脂酰丝氨酸的表达水平与对GW4869的敏感性密切相关。用布雷菲德菌素A抑制细胞表面磷脂酰丝氨酸的暴露会导致对GW4869产生抗性。最后，GW4869在体内可延缓磷脂酰丝氨酸水平高的骨髓瘤细胞的生长。据我们所知，这是利用小分子靶向恶性细胞上磷脂酰丝氨酸的首个实例。本研究可能为开发用于治疗表达表面磷脂酰丝氨酸的癌症的磷脂酰丝氨酸靶向小分子提供理论依据。
