Thus, TNF and IL-1 are multifunctional factors affecting various ovarian processes.

There is an urgent need to develop new strategies to treat ovarian cancer, the most deadly gynecologic malignancy. Histone deacetylase (HDAC) inhibitors are emerging as novel therapeutic drugs in the treatment of a variety of cancers, including those resistant to standard chemotherapy. Since there are multiple HDAC isoforms, determining the precise role of individual HDAC isoenzymes in the growth and progression of ovarian cancer has the potential to influence the use of selective HDAC inhibitors as strategic therapeutic agents that elicit fewer undesirable side effects. Unfortunately, there is limited information about the expression of HDAC isoforms in human ovarian tissues. This report provides evidence for the first time that Class I HDACs are expressed at significantly higher levels in ovarian cancers in comparison to normal ovarian tissues, with no significant difference in Class II HDAC expression between the two groups. Furthermore, ovarian cancer cells are far more sensitive than normal ovarian cells to the potent HDAC inhibitor romidepsin (FK228), a drug that displays greater inhibitory selectivity for Class I HDACs over Class II isoforms. Using small interfering RNA (siRNA) methodology, we demonstrate that knocking down the gene expression of HDAC3 and other members of the Class I HDAC family suppresses ovarian cancer cell growth. Taken together, the present studies offer several novel findings that have direct relevance for the strategic use of inhibitors that target Class I HDACs, particularly HDAC3, in the treatment of ovarian cancer.

Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions.

Chronic inflammation is an important underlying condition for ovarian tumor development, growth and progression. Since chemokine networks are activated by inflammation, patterns of chemokine gene expression were investigated in ovarian cancer cells. Chemokine specific microarrays were performed after mouse (ID8) and human (SKOV-3) ovarian surface epithelial cancer cells were exposed to the inflammatory agent bacterial endotoxin lipopolysaccharide (LPS, 10 microg/ml) and pro-inflammatory cytokines interleukin-1beta (IL-1, 10 ng/ml) and tumor necrosis factor-alpha (TNF, 10 ng/ml). In the mouse ID8 cells, LPS, IL-1 and TNF led to robust upregulation of keratinocyte chemoattractant (KC) chemokines CXCL1/2, mouse homologues of human growth-regulated oncogenes (GRO). Other chemokines, interferong inducible protein (IP)-10 (CXCL10), CCL7 and CCL20 were moderately upregulated. ID8 cells constitutively expressed CXCL16 and CCL2, but only CCL2 expression was enhanced by LPS, IL-1 and TNF. In the human SKOV-3 cells, LPS had no effect on chemokines expression due to the absence of the LPS receptor, toll-like receptor 4 (TLR4). However, IL-1 and TNF induced GROalpha/beta (CXCL1/2) in human SKOV-3 cells in a similar manner as observed with mouse ID8 cells. In SKOV-3 cells, IL-8 (CXCL8) was highly expressed and other chemokines GROgamma (CXCL3) and CCL20 were moderately expressed in response to IL-1 and TNF. The nuclear factor-kappaB (NF-kappaB) is a known mediator of cytokine and chemokines signaling. The NFkappaB inhibitor BAY 11-7082 attenuated expression of inflammatory-induced chemokines in the mouse and human ovarian cancer cells. Taken together, the results indicate that KC/GRO chemokines are the principal chemokines induced by LPS and pro-inflammatory cytokines IL-1 and TNF via NFkappaB signaling in ovarian surface epithelial cancer cells.