title: 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.affiliation: Protein Modification and Degradation Lab, Department of Pathophysiology, Guangzhou Medical College, Guangdong, People's Republic of China.
authors.forename: Hongbiao
authors.initials: H
authors.lastname: Huang
authors.forename: Ningning
authors.initials: N
authors.lastname: Liu
authors.forename: Changshan
authors.initials: C
authors.lastname: Yang
authors.forename: Siyan
authors.initials: S
authors.lastname: Liao
authors.forename: Haiping
authors.initials: H
authors.lastname: Guo
authors.forename: Kai
authors.initials: K
authors.lastname: Zhao
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Li
authors.forename: Shouting
authors.initials: S
authors.lastname: Liu
authors.forename: Lixia
authors.initials: L
authors.lastname: Guan
authors.forename: Chunjiao
authors.initials: C
authors.lastname: Liu
authors.forename: Li
authors.initials: L
authors.lastname: Xu
authors.forename: Change
authors.initials: C
authors.lastname: Zhang
authors.forename: Wenbin
authors.initials: W
authors.lastname: Song
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Tang
authors.forename: Q Ping
authors.initials: QP
authors.lastname: Dou
authors.forename: Jinbao
authors.initials: J
authors.lastname: Liu
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002331:Carnitine / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002843:Chromatin / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D061988:Proteasome Inhibitors; D011719:Pyrazines; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D000069286:Bortezomib; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; D002331:Carnitine