Chidamide, a histone deacetylase inhibitor, functions as a tumor inhibitor by modulating the ratio of Bax/Bcl-2 and P21 in pancreatic cancer.
Chidamide is a newly designed histone deacetylase (HDAC) inhibitor that has been applied in clinical trials. This study aimed to test the effect of Chidamide on proliferation and apoptosis in pancreatic cancer cell lines and in vivo tumors, as well as to determine the underlying mechanism. The PaTu8988 pancreatic tumor cell line either in culture or inoculated in nude mice were used to evaluate the antitumor characteristics of Chidamide. Proliferation and apoptosis of cultured PaTu8988 cells were examined by CCK-8 assay and Annexin V-FITC/PI double staining assay, respectively. Alterations in protein expression, including Caspase-3, Bcl-2‑like protein 4 (Bax), B-cell lymphoma 2 (Bcl-2) and p21, were tested by western blot analysis. The mRNA of different HDACs was examined by quantitative polymerase chain reaction (qPCR) experiments. Chidamide suppressed cell proliferation and induced early apoptosis of pancreatic tumor cells in a dose‑dependent manner after 48 h of treatment. Similarly, the in vivo study using pancreatic tumor murine model showed that Chidamide administration significantly inhibited the growth of pancreatic tumor and induced tumor cell apoptosis. The in vitro and in vivo studies found that Chidamide treatment significantly decreased the expression of type I HDACs, uncleaved Caspase-3 and p21 and increased the ratio of Bax/Bcl-2 expression. The results from the in vitro and in vivo studies suggested Chidamide might suppress the proliferation of pancreatic tumor cells by downregulating the expression of type I HDACs and p21, and promoting mitochondrial apoptosis pathway-dependent cell apoptosis in a dose-dependent manner. The study provided more evidence for clinical administration of Chidamide that targets pancreatic tumor cells and identified potential molecular targets for the development of potent anticancer drugs.
Department of General Surgery, Shanghai Seventh People's Hospital, Shanghai 200137, P.R. China.
Bin
B
Zhao
Department of General Surgery, Changhai Hospital, Shanghai 200433, P.R. China.
Tianlin
T
He
D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001549:Benzamides / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D000631:Aminopyridines; D000970:Antineoplastic Agents; C494826:BAX protein, human; C000595707:BCL2 protein, human; D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C547816:N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide; C505407:CASP3 protein, human; D053148:Caspase 3; D006655:Histone Deacetylases