In the United States, ovarian cancer is the most lethal gynecologic malignancy and represents the fifth leading cause of cancer death among women[1
]. Key goals in the management of this disease are prevention, early detection, and prolongation of disease-free intervals and overall survival upon development of the disease. Most primary ovarian cancers arise from malignant transformation of the surface epithelium. Although the specific molecular events responsible for this transformation remain unknown, two general theories have been proposed: incessant ovulation [2
] and excess gonadotropin secretion[4
]. Ovulation is essentially a natural inflammatory process; therefore a pro-inflammatory state is felt contribute to ovarian carcinogenesis[5
]. There is ample evidence that inflammation is causally linked to carcinogenesis [7
] in other tumor types, and targeting mediators of inflammation has been used as a strategy to both prevent and treat cancer.
Our understanding of ovarian cancer carcinogenesis is limited. Many of the genes that mediate inflammation and adaptive survival strategies in cancer cells including: self-sufficient growth, insensitivity to growth-inhibitory signals, evasion of apoptosis, limitless replicative potential, and sustained angiogenesis,[8
] are under the transcriptional control of NF-κB [9
]. Constitutive activation of NF-κB has been described in many tumor types including ovarian cancer [9
], suggesting that targeting NF-κB may have anti-inflammatory and anti-neoplastic effects in this tumor type.
Of late, several plant-derived extracts have been evaluated as possible inhibitors of the NF-κB pathway. Ginger root (Zingiber officinale
radix Roscoe) and its main poly-phenolic constituents (gingerols and zerumbone) have anti-oxidant [10
], anti-inflammatory [16
], and anti-carcinogenic activity [20
]. In particular, ginger root and its constituents can inhibit NF-κB activation induced by a variety of agents [25
], and has been shown to down regulate NF-κB regulated gene products involved in cellular proliferation and angiogenesis, including IL-8 [29
], and VEGF[30
]. These factors have also been shown to promote tumor cell proliferation, angiogenesis, and affect apoptotic response in ovarian cancers.
Among the myriad of pro-angiogenic cytokines known to induce tumor angiogenesis, vascular endothelial growth factor (VEGF) is the best characterized. In vitro
and in vivo
studies have shown that VEGF is critically involved in various steps of ovarian cancer carcinogenesis, and recent studies indicate that serum VEGF is an independent prognostic factor for patients with all stages of ovarian cancer [31
]. Interleukin-8 (IL-8) was originally found to function as a macrophage derived pro-angiogenic factor [32
], and has since been shown to affect cancer progression through mitogenic, angiogenic and motogenic effects[33
]. Increased blood levels of IL-8 have been found in ovarian cancer patients [34
], and IL-8 has been shown to stimulate proliferative growth in ovarian cancer cells in vitro
In the present study, we tested the hypothesis that ginger could exert inhibitory effects on cell growth, and modulate the production of angiogenic factors in epithelial ovarian cancer cells. Our data reveals that ginger significantly inhibits ovarian cancer cell growth, and that the major bio-active component of ginger is 6-shagoal. Moreover, ginger inhibits NF-κB activation and subsequent secretion of the angiogenic factors IL-8 and VEGF in ovarian cancer cells.