title: HDAC Inhibitor Oxamflatin Induces Morphological Changes and has Strong Cytostatic Effects in Ovarian Cancer Cell Lines.
abstract: Ovarian epithelial carcinoma is the leading cause of deaths from gynecologic malignancy. New reagents with therapeutic potentials against ovarian cancer, especially the drug-resistant cases, are required for better treatment of ovarian cancer patients. Epigenetic events such as changes in DNA methylation and histone modification, through their effects on DNA-protein interaction, chromatin conformation, and gene expression, affect cell function, cancer behavior, clinical manifestations, and outcomes. Previous studies have shown that histone deacetylase (HDAC) inhibitors have strong cytostatic and apoptotic activities in hematologic and some solid cancer cells. Oxamflatin, a compound containing the aromatic sulfonamide and hydroxamic acid groups, is known to be a potent HDAC inhibitor capable of inhibiting the growth of mouse and human cancer cell lines. In this study we found that oxamflatin in the nM range induced morphological changes in OVCAR-5 and SKOV-3 ovarian cancer cell lines. Treatment with oxamflatin also led to decreased cell viability. Moreover, results of BrdU incorporation assay, cell counting, and Ki-67 immunostaining indicated that oxamflatin was able to significantly inhibit DNA synthesis and cell proliferation. Using real-time PCR and Western blot analyses we demonstrated that oxamflatin was capable of downregulating the expression of c-Myc, CDK4, E2F1, and the phosphorylation levels of Rb protein, but upregulating p21. These findings pave the way to examine if oxamflatin along with or in combination with other reagents could deliver anticancer effects against ovarian cancers in vivo.
authors.affiliation: Department of Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China. yaliwang72@163.com.
authors.forename: Y-L
authors.initials: YL
authors.lastname: Wang
authors.forename: H-L
authors.initials: HL
authors.lastname: Liui
authors.forename: R-G
authors.initials: RG
authors.lastname: Fu
authors.forename: Z-W
authors.initials: ZW
authors.lastname: Wang
authors.forename: H-T
authors.initials: HT
authors.lastname: Ren
authors.forename: Z-J
authors.initials: ZJ
authors.lastname: Dai
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Jing
authors.forename: Y
authors.initials: Y
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019394:Ki-67 Antigen / Q000235:genetics / Q000378:metabolism; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004273:DNA, Neoplasm; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D019394:Ki-67 Antigen; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D016160:Retinoblastoma Protein; C100692:oxamflatin; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D006655:Histone Deacetylases