title: Chidamide and 5-flurouracil show a synergistic antitumor effect on human colon cancer xenografts in nude mice.
abstract: Chidamide is a novel histone deacetylase (HDAC) inhibitor that increases the acetylation of histone H3 by inhibiting the activity of HDAC1 and HDAC2. We previously found that treatment of human colon cancer cells with chidamide led to cell apoptosis and cell cycle arrest at G0/1 phase in vitro. The present study extended the observations in vivo and explored the underlying molecular mechanisms. In nude mice bearing human colon cancer LoVo cell xenografts, chidamide alone or in combination with 5-flurouracil (5-Fu) reduced the expression of HDAC1 and HDAC2, accompanied with increased acetylation of histone H3. Chidamide alone inhibited the tumor growth and induce cell apoptosis in tumor-bearing mice. Combined treatment of chidamide with 5-Fu enhanced the anti-tumor activity of 5-Fu. Western blotting analysis showed that chidamide alone or in combination with 5-Fu upregulated the expressions of cleaved Caspase-3 and cleaved poly-ADP (adenosine diphosphate)-ribose polymerase (PARP). In addition, chidamide alone or in combination with 5-Fu increased the p53, phosphorylated-p53 (p-p53), p21 and γH2AX levels, but suppressed cyclin dependent kinase 4 (CDK4) expression in tumor cells. Chidamide alone or in combination with 5-Fu down regulated the expressions of p-AKT, p-mammalian target of rapamycin (mTOR), p-p70S6K, p-Raf, and p44/42 mitogen activated protein kinase (Erk1/2), indicating the blockage of these signaling pathways. The results demonstrated that chidamide alone or in combination with 5-Fu exerted anti-tumor activity in nude mice bearing human colon cancer LoVo cell xenografts, and several signaling pathways might be involved in the chidamide-induced tumor growth inhibition and tumor cell apoptosis.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Qiu
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: Y
authors.initials: Y
authors.lastname: Zheng
authors.forename: X
authors.initials: X
authors.lastname: Su
authors.forename: B
authors.initials: B
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Chen
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D005472:Fluorouracil / Q000494:pharmacology*; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000187:drug effects; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000964:Antimetabolites, Antineoplastic; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006657:Histones; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide; D000071137:Poly (ADP-Ribose) Polymerase-1; D053148:Caspase 3; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D005472:Fluorouracil
keywords: 5-flurouracil.; HDAC inhibitor; chidamide; colon cancer