Douvas Michael G, Hogan Karen N, Ji YanShan, Hollenback David, Bonham Lynn, Singer Jack W, Mitchell Beverly S
Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, USA.
Leuk Res. 2006 Aug;30(8):1027-36. doi: 10.1016/j.leukres.2005.11.018. Epub 2006 Feb 20.
Phosphatidic acid (PA) is an important component of mammalian target of rapamycin (mTOR) signaling and in the recruitment of Raf to the cell membrane. PA can be produced by several mechanisms, including by a series of lysophosphatidic acid acyl transferases (LPAATs). LPAAT-beta is an isoform that is overexpressed in some human cancers and its inhibition has been investigated as a potential targeted cancer therapy. We report that LPAAT-protein and enzyme activity in acute leukemia cell lines and blasts from patient samples are equivalent to levels in normal mononuclear cells. Treatment with the LPAAT-beta inhibitor CT-32228 (Cell Therapeutics, Seattle, WA) uniformly induces apoptosis in multiple leukemia cell lines. In patient samples, however, apoptosis was variably induced by CT-32228 and appeared to be related to the degree of cellular proliferation. The growth inhibitory effect of CT-32228 on normal hematopoietic progenitors was more pronounced in cells induced to proliferate by growth factors. These data suggest that CT-32228 may have potential in the treatment of acute leukemias, but that efficacy is more directly related to the degree of cell proliferation rather than to the level of LPAAT-beta expression or activity.
磷脂酸（PA）是哺乳动物雷帕霉素靶蛋白（mTOR）信号传导以及Raf募集至细胞膜过程中的重要组成部分。PA可通过多种机制产生，包括一系列溶血磷脂酸酰基转移酶（LPAATs）。LPAAT-β是一种在某些人类癌症中过表达的亚型，其抑制作用已作为一种潜在的靶向癌症治疗方法进行了研究。我们报告，急性白血病细胞系以及患者样本中的原始细胞中的LPAAT-蛋白和酶活性与正常单核细胞中的水平相当。用LPAAT-β抑制剂CT-32228（细胞治疗公司，华盛顿州西雅图）处理可一致地诱导多种白血病细胞系发生凋亡。然而，在患者样本中，CT-32228可不同程度地诱导凋亡，且似乎与细胞增殖程度有关。CT-32228对正常造血祖细胞的生长抑制作用在由生长因子诱导增殖的细胞中更为明显。这些数据表明，CT-32228可能在急性白血病治疗中具有潜力，但疗效更直接地与细胞增殖程度相关，而非与LPAAT-β的表达或活性水平相关。
