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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.