Elena Rubatto
INTRODUCTION
In 2007 a group of reserchers pubblicated an article about the role of ginger in the treatment of ovarian cancer.
Ginger (Zingiber officinale Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-κB. NF-κB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. They investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells in vitro.
OVARIAN CANCER AND NF-KB
In the United States, ovarian cancer is the most lethal gynecologic malignancy and represents the fifth leading cause of cancer death among women.
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, are under the transcriptional control of NF-κB. Constitutive activation of NF-κB has been described in many tumor types including ovarian cancer, suggesting that targeting NF-κB may have anti-inflammatory and anti-neoplastic effects in this tumor type.
Results from many published studies describe indicated a definitive involvement of inflammatory pathway in the progression and treatment of ovarian cancer. Some anti-inflammatory phytochemicals exhibit the activities to intervene the dysregulated inflammation pathway and may play a beneficial role in the treatment of advanced EOC. However, there are many question remain to be answered. Further research in this area is urgently needed. Advances in treatment of ovarian cancer - a potential role of anti-inflammatory phytochemicals
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 (Preoperative serum vascular endothelial growth factor as a prognostic parameter in ovarian cancer). Interleukin-8 (IL-8) was originally found to function as a macrophage derived pro-angiogenic factor, and has since been shown to affect cancer progression through mitogenic, angiogenic and motogenic effects. Increased blood levels of IL-8 have been found in ovarian cancer patients, and IL-8 has been shown to stimulate proliferative growth in ovarian cancer cells in vitro (Regulatory effect of e2, IL-6 and IL-8 on the growth of epithelial ovarian cancer cells).
GINGER AND NF-KB
The study 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.
To determine the relative bio-activity in ovarian cancer, A2780 ovarian cancer cells were treated with 6-, 8- and 10-gingerol as well as 6-shogaol. The research shows that 6-, 8- and 10-gingerol had no effect on the growth or viability of ovarian cancer cells (p > .05 at all time points). Treating cells with whole ginger extract or 6-shogaol (figure1) resulted in profound growth inhibition. Morphologically, cells treated with ginger appeared markedly growth inhibited, similar to cisplatin (figure2) treated cells.
Cells cultured with vehicle control DMSO) continued to proliferate.
Because ginger markedly suppressed ovarian cancer cell proliferation in vitro, and several genes that regulate proliferation are regulated by NF-κB, they hypothesized that ginger may mediate its anti-neoplastic activity in ovarian cancer cells though modulation of this pathway. Constitutive activation of NF-κB has been described in many tumor types including ovarian cancer (NF-kappaB in solid tumors), suggesting that targeting NF-κB may have an anti-neoplastic effect in this tumor type. They chose two chemoresistant ovarian cancer cell lines (CaOV3 and SKOV3) to evaluate the effect of ginger treatment on activation of NF-κB. As shown in Figure3 treatment with ginger extract resulted in a significant inhibition of NF-κB activation in CaOV3 and SKOV3 cell lines.
Because IL-8 secretion is thought to be regulated in part by NF-κB, and ginger can clearly inhibit NF-κB in ovarian cancer cells, they hypothesized that ginger could also inhibit IL-8 secretion. Using a representative panel of ovarian cancer cell lines, they found that A2780 and CaOV3 cells produced negligible amounts of IL-8 (<0.05 pg/ml), whereas the cell lines ES-2 and SKOV3 had high constitutive expression of IL-8 (Figure4). Treatment with ginger resulted in significant inhibition of IL-8 production in the ES-2 and SKOV3 cell lines (p < .05 for both cell lines).
Because ginger treatment resulted in inhibition of NF-κB, they next sought to determine whether ginger could similarly inhibit VEGF in ovarian cancer cells. In all cell lines tested, there was high endogenous production of VEGF, and ginger treatment resulted in inhibition of VEGF secretion. Inhibition of VEGF secretion was most evident in the ES-2 cell line (p = .007), as compared to the other cell lines tested (p = .19, .18, and .07 for A2780, CaOV3, and SKOV3 respectively).
CONCLUSION
Many of the pathways that mediate adaptive survival strategies in cancer cells are under the transcriptional control of NF-κB. It has been shown that in ovarian cancer cells, NF-κB is constitutively activated, and blocking NF-κB activation with ginger results in suppressed production of NF κB regulated angiogenic factors and selectively inhibits ovarian cancer cell growth. Previous reports indicate that the ginger component 6-shogaol induces cell death in chemoresistant hepatoma cells, yet inhibits cell death in non-neoplastic spinal cord cells, suggesting that ginger and ginger components' effects are cell type specific. Phytochemicals such as ginger, generally have multiple molecular targets. This pleiotropism may constitute an advantage in the treatment of ovarian cancer, where multiple factors contribute towards the carcinogenic process.
The results of this study indicate that ginger may exhibit anti-neoplastic effects through the inhibition of NF-κB. Further studies utilizing ginger in an in vivo model of ovarian cancer will provide a platform for the development of ginger as a therapeutic tool in this disease.
Accumulating evidence suggests that many dietary factors may be used alone or in combination with traditional chemotherapeutic agents to prevent or treat cancer. For example the active component of chili peppers capsaicin has a very similar structure to 6-shagoal; his effect on cancer cells growth could be investigated in the future. The potential advantage of many natural or dietary compounds seems to focus on their potent anticancer activity combined with low toxicity and very few adverse side effects.
