Purpose: Lysophosphatidic acid acyltransferase (LPAAT)-β 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-β induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-β as a potential drug target in neoplasia. Experimental Design: In this study, we investigated the effects of CT32228, a specific LPAAT-β inhibitor, on BCR-ABL-transformed cell lines and primary cells from patients with chronic myelogenous leukemia. Results: CT32228 had antiproliferative activity against BCR-ABL-postive 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-β as a potential drug target for the treatment of BCR-ABL-positive leukemias.
ASJC Scopus subject areas
- Cancer Research