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Updated: Aug 11, 2026
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
Effect of lysophosphatidic acid acyltransferase-beta inhibition in acute leukemia
Michael G Douvas1, Karen N Hogan, YanShan Ji
1Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, USA. mgd9a@virginia.edu
Abstract:
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.
Insights
Lysophosphatidic acid acyl transferase-beta (LPAAT-beta) inhibitor CT-32228 induces apoptosis in leukemia cells. Its efficacy in acute leukemia patients depends on cell proliferation, not LPAAT-beta levels.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Phosphatidic acid (PA) is integral to mammalian target of rapamycin (mTOR) signaling and Raf recruitment.
- Lysophosphatidic acid acyl transferases (LPAATs) produce PA; LPAAT-beta is overexpressed in some cancers.
- LPAAT-beta inhibition is explored as a targeted cancer therapy.
Purpose of the Study:
- To investigate LPAAT-beta expression and activity in acute leukemia.
- To evaluate the efficacy of the LPAAT-beta inhibitor CT-32228 in acute leukemia models.
- To determine factors influencing CT-32228's therapeutic effect.
Main Methods:
- Assessed LPAAT-protein and enzyme activity in leukemia cell lines and patient samples.
- Treated leukemia cell lines and patient samples with CT-32228.
- Evaluated apoptosis induction and cellular proliferation.
- Assessed CT-32228's effect on normal hematopoietic progenitors.
Main Results:
- LPAAT-beta expression and activity were similar in leukemia and normal cells.
- CT-32228 induced apoptosis in leukemia cell lines.
- Apoptosis induction in patient samples varied and correlated with proliferation.
- CT-32228 inhibited normal hematopoietic progenitors more significantly in proliferating cells.
Conclusions:
- LPAAT-beta levels do not predict CT-32228 response in acute leukemia.
- CT-32228 shows potential for treating acute leukemias.
- Therapeutic efficacy of CT-32228 is linked to cancer cell proliferation rates.
