title: Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of myc-induced lymphomagenesis.
abstract: BACKGROUND
  The metabolic alterations of cancer cells represent an opportunity for developing selective antineoplastic treatments. We investigated the therapeutic potential of ST1326, an inhibitor of carnitine-palmitoyl transferase 1A (CPT1A), the rate-limiting enzyme for fatty acid (FA) import into mitochondria.
  
  
  METHODS
  ST1326 was tested on in vitro and in vivo models of Burkitt's lymphoma, in which c-myc, which drives cellular demand for FA metabolism, is highly overexpressed. We performed assays to evaluate the effect of ST1326 on proliferation, FA oxidation, and FA mitochondrial channeling in Raji cells. The therapeutic efficacy of ST1326 was tested by treating Eµ-myc mice (control: n = 29; treatment: n = 24 per group), an established model of c-myc-mediated lymphomagenesis. Experiments were performed on spleen-derived c-myc-overexpressing B cells to clarify the role of c-myc in conferring sensitivity to ST1326. Survival was evaluated with Kaplan-Meier analyses. All statistical tests were two-sided.
  
  
  RESULTS
  ST1326 blocked both long- and short-chain FA oxidation and showed a strong cytotoxic effect on Burkitt's lymphoma cells (on Raji cells at 72 hours: half maximal inhibitory concentration = 8.6 μM). ST1326 treatment induced massive cytoplasmic lipid accumulation, impairment of proper mitochondrial FA channeling, and reduced availability of cytosolic acetyl coenzyme A, a fundamental substrate for de novo lipogenesis. Moreover, treatment with ST1326 in Eµ-myc transgenic mice prevented tumor formation (P = .01), by selectively impairing the growth of spleen-derived primary B cells overexpressing c-myc (wild-type cells + ST1326 vs. Eµ-myc cells + ST1326: 99.75% vs. 57.5%, difference = 42.25, 95% confidence interval of difference = 14% to 70%; P = .01).
  
  
  CONCLUSIONS
  Our data indicate that it is possible to tackle c-myc-driven tumorigenesis by altering lipid metabolism and exploiting the neoplastic cell addiction to FA oxidation.
authors.affiliation: Dipartimento di Patologia Sperimentale, Università di Bologna, Via San Giacomo 14, 40126, Bologna, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pacilli
authors.forename: Maria
authors.initials: M
authors.lastname: Calienni
authors.forename: Sabrina
authors.initials: S
authors.lastname: Margarucci
authors.forename: Maria
authors.initials: M
authors.lastname: D'Apolito
authors.forename: Orsolina
authors.initials: O
authors.lastname: Petillo
authors.forename: Laura
authors.initials: L
authors.lastname: Rocchi
authors.forename: Gianandrea
authors.initials: G
authors.lastname: Pasquinelli
authors.forename: Raffaella
authors.initials: R
authors.lastname: Nicolai
authors.forename: Aleardo
authors.initials: A
authors.lastname: Koverech
authors.forename: Menotti
authors.initials: M
authors.lastname: Calvani
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Peluso
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Montanaro
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D002333:Carnitine Acyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D045744:Cell Line, Tumor; D005227:Fatty Acids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D010084:Oxidation-Reduction; D016271:Proto-Oncogene Proteins c-myc / Q000187:drug effects / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D016588:Anticarcinogenic Agents; D005227:Fatty Acids; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C511293:ST1326; D002333:Carnitine Acyltransferases; C577474:CPT1A protein, human; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine