ct-32228 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

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.. 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.. 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.. These data establish LPAAT-beta as a potential drug target for the treatment of BCR-ABL-positive leukemias.

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