HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.

Abstract

Combinations of proteasome inhibitors and histone deacetylases (HDAC) inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC) is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel) was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21(cip1) gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like) activity assay. Here we report that (i) the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii) the combination also synergistically inhibits tumor growth in vivo; (iii) two major pathways are involved in the synergistical effects of the combinational treatment: increased p21(cip1) expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.

• Authors: Hongbiao Huang, Ningning Liu, Changshan Yang, Siyan Liao, Haiping Guo, Kai Zhao, Xiaofen Li, Shouting Liu, Lixia Guan, Chunjiao Liu, Li Xu, Change Zhang, Wenbin Song, Bing Li, Ping Tang, Q Ping Dou, Jinbao Liu
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e52576 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23285100 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• Chromatin
• Cyclin-Dependent Kinase Inhibitor p21
• Histone Deacetylase Inhibitors
• Histones
• Proteasome Inhibitors
• Pyrazines
• RNA, Small Interfering
• bcl-2-Associated X Protein
• Bortezomib
• Poly(ADP-ribose) Polymerases
• Caspases
• Carnitine

Topics

• Acetylation (drug effects)
• Animals
• Antineoplastic Agents (pharmacology)
• Boronic Acids (pharmacology)
• Bortezomib
• Carnitine (pharmacology)
• Caspases (metabolism)
• Cell Death (drug effects)
• Cell Proliferation (drug effects)
• Chromatin (metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (genetics, metabolism)
• Drug Synergism
• Endoplasmic Reticulum Stress (drug effects)
• Enzyme Activation (drug effects)
• Hep G2 Cells
• Histone Deacetylase Inhibitors (pharmacology)
• Histones (metabolism)
• Humans
• Male
• Mice
• Models, Biological
• Poly(ADP-ribose) Polymerases (metabolism)
• Proteasome Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• RNA, Small Interfering (metabolism)
• Unfolded Protein Response (drug effects)
• Xenograft Model Antitumor Assays
• bcl-2-Associated X Protein (metabolism)