PMID- 23486551
OWN - NLM
STAT- MEDLINE
DCOM- 20130520
LR  - 20220317
IS  - 1460-2105 (Electronic)
IS  - 0027-8874 (Linking)
VI  - 105
IP  - 7
DP  - 2013 Apr 3
TI  - Carnitine-acyltransferase system inhibition, cancer cell death, and prevention of 
      myc-induced lymphomagenesis.
PG  - 489-98
LID - 10.1093/jnci/djt030 [doi]
AB  - 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 Emicro-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 muM). 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 Emicro-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. Emicro-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.
FAU - Pacilli, Annalisa
AU  - Pacilli A
AD  - Dipartimento di Patologia Sperimentale, Universita di Bologna, Via San Giacomo 
      14, 40126, Bologna, Italy.
FAU - Calienni, Maria
AU  - Calienni M
FAU - Margarucci, Sabrina
AU  - Margarucci S
FAU - D'Apolito, Maria
AU  - D'Apolito M
FAU - Petillo, Orsolina
AU  - Petillo O
FAU - Rocchi, Laura
AU  - Rocchi L
FAU - Pasquinelli, Gianandrea
AU  - Pasquinelli G
FAU - Nicolai, Raffaella
AU  - Nicolai R
FAU - Koverech, Aleardo
AU  - Koverech A
FAU - Calvani, Menotti
AU  - Calvani M
FAU - Peluso, Gianfranco
AU  - Peluso G
FAU - Montanaro, Lorenzo
AU  - Montanaro L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130313
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Anticarcinogenic Agents)
RN  - 0 (Fatty Acids)
RN  - 0 (MYC protein, human)
RN  - 0 (Proto-Oncogene Proteins c-myc)
RN  - 0 (ST1326)
RN  - EC 2.3.1.- (Carnitine Acyltransferases)
RN  - EC 2.3.1.21 (CPT1A protein, human)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
RN  - S7UI8SM58A (Carnitine)
SB  - IM
MH  - Animals
MH  - Anticarcinogenic Agents/*pharmacology
MH  - Apoptosis/*drug effects
MH  - B-Lymphocytes/drug effects/metabolism
MH  - Blotting, Western
MH  - Burkitt Lymphoma/*enzymology/metabolism/pathology/*prevention & control
MH  - Carnitine/*analogs & derivatives/pharmacology
MH  - Carnitine Acyltransferases/antagonists & inhibitors/metabolism
MH  - Carnitine O-Palmitoyltransferase/*antagonists & inhibitors/*metabolism
MH  - Cell Line, Tumor
MH  - Fatty Acids/metabolism
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Kaplan-Meier Estimate
MH  - Lipid Metabolism/*drug effects
MH  - Mice
MH  - Oxidation-Reduction
MH  - Proto-Oncogene Proteins c-myc/drug effects/*metabolism
MH  - Real-Time Polymerase Chain Reaction
MH  - Treatment Outcome
MH  - Up-Regulation
EDAT- 2013/03/15 06:00
MHDA- 2013/05/22 06:00
CRDT- 2013/03/15 06:00
PHST- 2013/03/15 06:00 [entrez]
PHST- 2013/03/15 06:00 [pubmed]
PHST- 2013/05/22 06:00 [medline]
AID - djt030 [pii]
AID - 10.1093/jnci/djt030 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 2013 Apr 3;105(7):489-98. doi: 10.1093/jnci/djt030. Epub 2013 
      Mar 13.