Effect of lysophosphatidic acid acyltransferase-beta inhibition in acute leukemia.
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.
Douvas
Michael G
MG
Department of Pediatrics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill School of Medicine, USA. mgd9a@virginia.edu
Hogan
Karen N
KN
Ji
YanShan
Y
Hollenback
David
D
Bonham
Lynn
L
Singer
Jack W
JW
Mitchell
Beverly S
BS
D000208:Acute Disease; D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000494:pharmacology*
C505793:CT-32228; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D014227:Triazines; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase