Targeting the leukemia cell metabolism by the CPT1a inhibition: functional preclinical effects in leukemias.
Cancer cells are characterized by perturbations of their metabolic processes. Recent observations demonstrated that the fatty acid oxidation (FAO) pathway may represent an alternative carbon source for anabolic processes in different tumors, therefore appearing particularly promising for therapeutic purposes. Because the carnitine palmitoyl transferase 1a (CPT1a) is a protein that catalyzes the rate-limiting step of FAO, here we investigated the in vitro antileukemic activity of the novel CPT1a inhibitor ST1326 on leukemia cell lines and primary cells obtained from patients with hematologic malignancies. By real-time metabolic analysis, we documented that ST1326 inhibited FAO in leukemia cell lines associated with a dose- and time-dependent cell growth arrest, mitochondrial damage, and apoptosis induction. Data obtained on primary hematopoietic malignant cells confirmed the FAO inhibition and cytotoxic activity of ST1326, particularly on acute myeloid leukemia cells. These data suggest that leukemia treatment may be carried out by targeting metabolic processes.
Hematology, "Sant'Andrea" Hospital-Sapienza, University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy;
Maria Rosaria
http://orcid.org/0000-0002-8772-3521
MR
Ricciardi
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy;
Simone
http://orcid.org/0000-0002-8742-4118
S
Mirabilii
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy;
Matteo
M
Allegretti
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy;
Roberto
R
Licchetta
Italian National Council of Research (NCR), Institute of Biosciences and BioResources-CNR, Naples, Italy; and.
Anna
A
Calarco
Hematology, "Sant'Andrea" Hospital-Sapienza, University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy;
Maria Rosaria
MR
Torrisi
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy;
Robin
R
Foà
Sigma-Tau Pharmaceutical Industries Pomezia S.p.A., Pomezia, Italy.
Raffaella
R
Nicolai
Italian National Council of Research (NCR), Institute of Biosciences and BioResources-CNR, Naples, Italy; and.
Gianfranco
G
Peluso
Hematology, "Sant'Andrea" Hospital-Sapienza, University of Rome, Department of Clinical and Molecular Medicine, Rome, Italy;
Agostino
http://orcid.org/0000-0001-7911-9263
A
Tafuri
D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects
D005227:Fatty Acids; D009363:Neoplasm Proteins; C511293:ST1326; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine