Antileukemic Activity of Lysophosphatidic Acid Acyltransferase-β Inhibitor CT32228 in Chronic Myelogenous Leukemia Sensitive and Resistant to Imatinib

Abstract

Purpose: Lysophosphatidic acid acyltransferase (LPAAT)-β catalyzes the conversion of lysophosphatidic acid to phosphatidic acid, an essential component of several signaling pathways, including the Ras/mitogen-activated protein kinase pathway. Inhibition of LPAAT-β induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-β as a potential drug target in neoplasia. Experimental Design: In this study, we investigated the effects of CT32228, a specific LPAAT-β inhibitor, on BCR-ABL-transformed cell lines and primary cells from patients with chronic myelogenous leukemia. Results: CT32228 had antiproliferative activity against BCR-ABL-positive cell lines in the nanomolar dose range, evidenced by cell cycle arrest in G2-M and induction of apoptosis. Treatment of K562 cells with CT32228 led to inhibition of extracellular signal-regulated kinase 1/2 phosphorylation, consistent with inhibition of mitogen-activated protein kinase signaling. Importantly, CT32228 was highly active in cell lines resistant to the Bcr-Abl kinase inhibitor imatinib. Combination of CT32228 with imatinib produced additive inhibition of proliferation in cell lines with residual sensitivity toward imatinib. In short-term cultures in the absence of growth factors, CT32228 preferentially inhibited the growth of granulocyte-macrophage colony-forming units from chronic myelogenous leukemia patients compared with healthy controls. Conclusion: These data establish LPAAT-β as a potential drug target for the treatment of BCR-ABL-positive leukemias.

Molecular Pathways: Targeting Diacylglycerol Kinase Alpha in Cancer

“…In addition to the DGKs, the lysophosphatidic acid acyltransferases (LPAATs) and phospholipase D (PLD) enzymes also generate PA. LPAAT and PLD enzymes have also been linked to cancer, further supporting roles for PA in malignant cells (21–24). Though all DGKs convert DAG to PA, they may still play unique roles in cancer given their different cellular localizations.…”

Mammalian Triacylglycerol Metabolism: Synthesis, Lipolysis, and Signaling

“…400 Thus, small molecule inhibitors that cause apoptosis have been tested for a possible therapeutic role. 399–402 …”

Thematic Review Series: Glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity

“…For example, genes encoding enzymes in the triglyceride biosynthetic pathway have been shown to be mutated in human and mouse lipodystrophy syndromes (LPIN1, AGPAT2) (18,19), and polymorphisms in both LPIN1 and LPIN2 genes have been linked to body weight and insulin sensitivity (20). Genes encoding enzymes in the triglyceride biosynthetic pathway have also been linked to inflammatory disorders (LPIN2, AGPAT2) (21,22) and survival of certain cancers (AGPAT2) (23,24). Since deletion (25) or inhibition (26) of diacylglycerol acyltransferase 1 (DGAT1) in mouse decreases body weight and improves insulin resistance, there has been intense interest in the development of DGAT1 inhibitors for the treatment of obesity and type 2 diabetes.…”