Effect of lysophosphatidic acid acyltransferase-β inhibition in acute leukemia
| Autor: | Beverly S. Mitchell, Jack W. Singer, Lynn Bonham, Karen N. Hogan, Yanshan Ji, David Hollenback, Michael Gregory Douvas |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Cell Apoptosis HL-60 Cells Biology Structure-Activity Relationship chemistry.chemical_compound Cell Line Tumor Lysophosphatidic acid medicine Humans Enzyme Inhibitors Progenitor cell PI3K/AKT/mTOR pathway Acute leukemia Leukemia Dose-Response Relationship Drug Hydrocarbons Halogenated Triazines Cell growth Hematology Enzyme Activation Haematopoiesis medicine.anatomical_structure Oncology chemistry Biochemistry Acute Disease Cancer research Acyltransferases |
| Zdroj: | Leukemia Research. 30:1027-1036 |
| ISSN: | 0145-2126 |
| DOI: | 10.1016/j.leukres.2005.11.018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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