Antileukemic activity of lysophosphatidic acid acyltransferase-beta inhibitor CT32228 in chronic myelogenous leukemia sensitive and resistant to imatinib.
OBJECTIVE
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.


METHODS
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 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.


CONCLUSIONS
These data establish LPAAT-beta as a potential drug target for the treatment of BCR-ABL-positive leukemias.
La Rosée
Paul
P
Division of Hematology and Medical Oncology, Oregon Health and Sciences University, Portland, Oregon.
Jia
Taiping
T
Demehri
Shadmer
S
Härtel
Nicolai
N
de Vries
Peter
P
Bonham
Lynn
L
Hollenback
David
D
Singer
Jack W
JW
Melo
Junia V
JV
Druker
Brian J
BJ
Deininger
Michael W
MW
D000217:Acyltransferases / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000494:pharmacology*; D000068877:Imatinib Mesylate; D015151:Immunoblotting; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; C505793:CT-32228; D004791:Enzyme Inhibitors; D006846:Hydrocarbons, Halogenated; D010879:Piperazines; D011743:Pyrimidines; D014227:Triazines; D000068877:Imatinib Mesylate; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; D048049:Extracellular Signal-Regulated MAP Kinases