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La Ros??e, P. et al.

Antileukemic Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitor CT32228 in Chronic Myelogenous Leukemia Sensitive and Resistant to Imatinib.

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 G(2)-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.[1]

References

Antileukemic Activity of Lysophosphatidic Acid Acyltransferase-{beta} Inhibitor CT32228 in Chronic Myelogenous Leukemia Sensitive and Resistant to Imatinib. La Ros??e, P., Jia, T., Demehri, S., H??rtel, N., de Vries, P., Bonham, L., Hollenback, D., Singer, J.W., Melo, J.V., Druker, B.J., Deininger, M.W. Clin. Cancer Res. (2006) [Pubmed]

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