L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro

L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatm...

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Published in:PloS one 2012-11, Vol.7 (11), p.e49062
Main Authors: Huang, Hongbiao, Liu, Ningning, Guo, Haiping, Liao, Siyan, Li, Xiaofen, Yang, Changshan, Liu, Shouting, Song, Wenbin, Liu, Chunjiao, Guan, Lixia, Li, Bing, Xu, Li, Zhang, Change, Wang, Xuejun, Dou, Q Ping, Liu, Jinbao
Format: Article
Language:English
Subjects:
Accumulation
Acetylation
Acetylation - drug effects
Adenosine Triphosphate - metabolism
Animals
Apoptosis
Assaying
ATP
Biocompatibility
Biology
Cancer
Carnitine
Carnitine - pharmacology
Cell cycle
Cell death
Cell growth
Cell Line, Tumor
Cell Proliferation - drug effects
Chromatin
Chromatin - metabolism
Citric acid
Cyclin-dependent kinase inhibitor p21
Cyclin-Dependent Kinase Inhibitor p21 - genetics
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Cyclin-dependent kinase inhibitor p27
Cyclin-Dependent Kinase Inhibitor p27 - genetics
Cytometry
Cytotoxicity
DNA microarrays
Energy (Physics)
Fatty acids
Flow cytometry
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Glucose metabolism
Glycolysis
Growth
GTP-binding protein
Hepatoma
High-performance liquid chromatography
Histone deacetylase
Histone Deacetylase Inhibitors - pharmacology
Histone Deacetylases - metabolism
Histones
Histones - metabolism
Humans
In vivo methods and tests
Inhibitors
Levocarnitine
Liquid chromatography
Lysine
Male
Medicine
Metabolism
Mice
Mice, Inbred BALB C
Mitochondria
Molecular docking
Molecular Docking Simulation
Neoplasms - enzymology
Neoplasms - genetics
Neoplasms - pathology
Nutrition
Polyclonal antibodies
Proteins
RNA
RNA, Messenger - genetics
RNA, Messenger - metabolism
Toxicity
Tricarboxylic acid cycle
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Summary:L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21(cip1) gene, mRNA and protein in cancer cells but not p27(kip1); (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21(cip1) gene but not p27(kip1) detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0049062