This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by La Rosée, P. Articles by Deininger, M. W. Search for Related Content PubMed PubMed Citation Articles by La Rosée, P. Articles by Deininger, M. W.

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

Authors' Affiliations: ¹ Division of Hematology and Medical Oncology, Oregon Health and Sciences University, Portland, Oregon; ² III. Medizinische Universitätsklinik, Fakultät für klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany; ³ Cell Therapeutics, Inc., Seattle, Washington; ⁴ Imperial College, Hammersmith Hospital, London, United Kingdom; and ⁵ Howard Hughes Medical Institute, Chicago, IL

Requests for reprints: Michael W. Deininger, Division of Hematology and Medical Oncology, Oregon Health and Science University Cancer Institute, Mail Code L592, 3181 Sam Jackson Park Road, Portland, OR 97239. Phone: 503-494-1603; Fax: 503-494-3366; E-mail: deinige{at}ohsu.edu.

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

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

This article has been cited by other articles:

				R. E. Gimeno and J. Cao Thematic Review Series: Glycerolipids. Mammalian glycerol-3-phosphate acyltransferases: new genes for an old activity J. Lipid Res., October 1, 2008; 49(10): 2079 - 2088. [Abstract] [Full Text] [PDF]