Antileukemic activity of lysophosphatidic acid acyltransferase-beta inhibitor CT32228 in chronic myelogenous leukemia sensitive and resistant to imatinib

Clin Cancer Res. 2006 Nov 1;12(21):6540-6. doi: 10.1158/1078-0432.CCR-06-0140.

Abstract

Purpose: Lysophosphatidic acid acyltransferase (LPAAT)-beta 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-beta induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-beta as a potential drug target in neoplasia.

Experimental design: In this study, we investigated the effects of CT32228, a specific LPAAT-beta 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-beta as a potential drug target for the treatment of BCR-ABL-positive leukemias.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / pharmacology*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Benzamides
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Hematopoietic Stem Cells / drug effects
  • Humans
  • Hydrocarbons, Halogenated / pharmacology*
  • Imatinib Mesylate
  • Immunoblotting
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy*
  • Phosphorylation / drug effects
  • Piperazines / pharmacology*
  • Pyrimidines / pharmacology*
  • Triazines / pharmacology*

Substances

  • Antineoplastic Agents
  • Benzamides
  • CT-32228
  • Enzyme Inhibitors
  • Hydrocarbons, Halogenated
  • Piperazines
  • Pyrimidines
  • Triazines
  • Imatinib Mesylate
  • Acyltransferases
  • 2-acylglycerophosphate acyltransferase
  • Extracellular Signal-Regulated MAP Kinases