Modulation of inflammatory signaling pathways by phytochemicals in ovarian cancer
© Springer-Verlag 2011
Received: 8 October 2010
Accepted: 4 January 2011
Published: 4 February 2011
Inflammation has been suggested to be involved in cancer development and progression. Many clinical and experimental studies have shown that inflammation could contribute to ovarian carcinogenesis through activation of the NF-κB and AP-1 pathways by chronic inflammatory mediators. Phytochemicals, which are natural compounds derived from fruits and vegetables, have shown anti-inflammatory and anti-cancer effects. Due to their relatively low toxicity and easy accessibility, phytochemicals have been investigated for their chemopreventive potential against various cancers. In this review, we discuss the role of phytochemicals in preventing ovarian cancer through anti-inflammatory mechanisms.
Ovarian cancer is the fifth leading cause of cancer deaths in women and is the most lethal gynecologic malignancy . The poor prognosis of ovarian cancer results mainly from the high percentage of cases diagnosed at an advanced stage. Although most patients with advanced ovarian cancer respond to first-line chemotherapy, 80% of patients will ultimately succumb to death due to recurrence.
Chemoprevention refers to the use of natural or synthetic agents to inhibit, delay, or reverse the development of cancer. There have been numerous in vitro and animal studies evaluating the efficacy of chemopreventive agents, including natural compounds, hormones, or other targeted agents, in various cancer models. Phytochemicals, which are natural compounds derived from fruits and vegetables, have been extensively investigated for their anti-cancer activities due to their safety, low toxicity, and general availability . The major dietary sources of phytochemicals include garlic, soybeans, ginger, grapes, green tea, turmeric, and cruciferous vegetables . These natural compounds have been reported to target multiple signaling pathways involved in carcinogenesis, such as cell proliferation, apoptosis, angiogenesis, and inflammatory signaling pathways. Given the complexity of crosstalk between cell signaling pathways in individual cancers, phytochemicals that affect diverse pathways have the advantage in chemoprevention over targeted agents, which inhibit single pathways and, therefore, have shown only modest inhibitory effects on tumor growth.
In ovarian cancer, chemoprevention is also gaining interest due to the limitations of current therapeutic modalities in improving survival outcomes, as well as the lack of efficient screening strategies. In this review, we will discuss the role of phytochemicals in the chemoprevention of ovarian cancer, especially in the context of their anti-inflammatory functions.
Ovarian carcinogenesis and inflammation
There have been several hypotheses about the underlying mechanisms of ovarian carcinogenesis. The first to arise was the ovulation hypothesis, which relates ovarian cancer risk to incessant ovulation . To support this hypothesis, there has been substantial epidemiologic evidence demonstrating that oral contraceptive use or multiple pregnancies can decrease cancer risk. Other stimulating factors, such as gonadotropin or hormones, have also been suggested to increase the risk of ovarian cancer [53, 66]. Recently, however, another compelling hypothesis has highlighted the role of inflammation in the development of ovarian cancer .
Inflammation in ovarian cancer
Inflammation has been suggested to contribute to every step of carcinogenesis, including tumor initiation, promotion, and progression . Components of the inflammatory pathway, including free radicals, cytokines, NF-κB, signal transducer and activator of transcription-3 (STAT-3), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandins, and vascular endothelial growth factor (VEGF), have been shown to contribute to the development of various malignancies, including ovarian cancer. In ovarian cancer samples, COX-2 was found to be highly expressed in nonmucinous ovarian cancers, and the expression of COX-2 was correlated with poor prognostic factors, such as stage, residual disease status, and presence of ascites .
The ovulation process itself is believed to be associated with inflammatory pathways. Ovarian surface epithelium adjacent to the site of ovulation may be exposed to inflammatory cytokines and prostaglandins and may undergo active replication, thereby enhancing the risk of malignant transformation. In addition, there is epidemiologic evidence supporting the role of inflammation in ovarian carcinogenesis . Some risk factors, including talc/asbestos exposure, endometriosis, and pelvic inflammatory disease, are known to enhance local inflammation, but not directly affect ovulation and hormone levels. Moreover, several studies have shown the inverse relationship between long-term nonsteroidal anti-inflammatory drug (NSAID) use and ovarian cancer risk [14, 52]. The proposed molecular targets of NSAIDs include NF-κB, iNOS, COX-2, and VEGF .
Phytochemicals targeting inflammatory signaling pathways
Based on the accumulating data supporting the role of inflammation in cancer development, clinical trials on chemoprevention of various malignancies utilizing NSAIDs or COX-2 inhibitors have been conducted , and celecoxib, a selective COX-2 inhibitor, has been shown to be effective in reducing the occurrence of colorectal adenomas . Despite their anti-cancer potential, however, clinical trials using COX-2 inhibitors, such as celecoxib and rofecoxib, were closed early due to the significantly increased risk of serious cardiovascular events [39, 60]. As a result, researchers have turned their interest to phytochemicals, with their more acceptable safety profiles, and have started to investigate their chemopreventive activities.
Curcumin, a component of turmeric, has traditionally been used as an anti-inflammatory drug. In addition to suppressing inflammation, recent studies have demonstrated that curcumin exhibits diverse activities, including antioxidant, anti-proliferative, and antiangiogenic activities, through interaction with multiple signaling pathways [32, 50]. The molecular targets of curcumin include transcription factors, growth factors, cytokines, enzymes, and other gene products .
NF-κB is a transcription factor and plays a key role in inflammation and cancer development by inducing several genes associated with anti-apoptosis, cell proliferation, angiogenesis, and metastasis . Curcumin has been shown to inhibit NF-κB activation induced by tumor necrosis factor (TNF), phorbol ester, hydrogen peroxide, or interleukin (IL)-1 in several cell lines [29, 57]. The inhibitory effect of curcumin on NF-κB activation is believed to be due to the inhibition of I-κB kinase (IKK) activity [29, 47, 58]. In multiple myeloma and melanoma cells, curcumin down-regulated NF-κB and prevented nuclear translocation of p65 through the suppression of IKK activity [7, 46]. Down-regulated NF-κB, in turn, leads to decreased expression of inflammatory enzymes, such as COX-2 and iNOS [10, 47, 55, 67].
Likewise, curcumin has been shown to inhibit NF-κB activation in ovarian cancer cells [30, 36]. In several ovarian cancer cell lines (SKOV3ip1 and HeyA8), curcumin suppressed NF-κB and STAT-3 activation and inhibited expression of COX-2 . EF24, a synthetic analog of curcumin, blocked the nuclear translocation of NF-κB and inhibited TNF-α-induced I-κB degradation through direct inhibition of IKK activity . Since NF-κB is also a transcription factor for inflammatory cytokines, curcumin has been demonstrated to attenuate the expression of IL-1, IL-6, and TNF-α . Curcumin increased the sensitivity of SKOV3 and CAOV3 cells to cisplatin, and one of the suggested mechanisms was reducing the production of IL-6 . In addition to inhibition of inflammatory cytokines, curcumin has also been shown to suppress angiogenic factors, such as VEGF, and subsequently inhibits angiogenesis in both in vitro and in vivo studies [36, 63].
In addition, there have been several animal studies demonstrating the anti-cancer effects of curcumin in skin, breast, and colon cancer models, mainly through anti-inflammatory effects [3, 13, 31, 48]. In a breast cancer model, dietary administration of curcumin to nude mice significantly reduced the incidence of lung metastasis, possibly through the inhibition of paclitaxel-induced expression of NF-κB, COX-2, and MMP9 . Similarly, in patients with pancreatic cancer, curcumin down-regulated the expression of NF-κB, COX-2, and phosphorylated STAT-3 in peripheral blood mononuclear cells . In an orthotopic murine model of ovarian cancer, curcumin demonstrated inhibitory effects on tumor growth and angiogenesis . In this study, treatment with curcumin alone or in combination with docetaxel significantly reduced the proliferation and microvessel density and increased tumor cell apoptosis in multidrug-resistant ovarian cancer tumors.
Resveratrol, a phytoalexin abundantly found in grape skins and red wine, has been shown to have anti-inflammatory and anti-carcinogenic properties . Resveratrol inhibits proliferation and induces apoptosis in various cancer cell lines, including breast, prostate, colon, and ovarian cancer cells . In nude mice implanted with human ovarian cancer cells, resveratrol suppressed tumor growth when it was administered intraperitoneally, and apoptotic features were observed in the tumor tissues [22, 34]. Resveratrol also enhanced the efficacy of cisplatin and doxorubicin in ovarian cancer cells, while reducing the doxorubicin-related cardiac toxicity .
The inhibitory effects of resveratrol on tumor growth have been, in part, attributed to its anti-inflammatory activity . In murine and human macrophage cells, resveratrol down-regulates NF-κB activity in a dose-dependent manner, which coincides with suppression of AP-1 [24, 38, 65]. Similar to curcumin, inhibition of NF-κB activity by resveratrol is considered to be mediated by blocking IKK activity . Resveratrol also suppresses expression of inflammatory enzymes, such as iNOS and COX-2, in macrophages and various cancer cells through the inhibition of NF-κB activity [35, 40, 61]. In ovarian cancer cells, resveratrol inhibits the expression of both basal level and growth factor–induced hypoxia-inducible factor-1α (HIF-1α) [8, 45]. The underlying mechanism appears to be associated with the inactivation of mitogen-activated protein kinase (MAPK) and protein translational regulator p70S6K, as well as enhanced degradation of HIF-1α protein through the proteasome pathway. Resveratrol also significantly suppresses vascular endothelial growth factor (VEGF) expression through inhibition of HIF-1α.
Taken together, these data suggest that resveratrol may inhibit ovarian carcinogenesis by down-regulating NF-κB activity and suppressing HIF-1α and VEGF expression.
Genistein is a soy-derived isoflavone and has shown protective effects against endocrine-related gynecological cancers [41, 68]. A meta-analysis study demonstrated an inverse correlation between soy intake and ovarian cancer risk.
Genistein has been shown to inhibit cell proliferation, cause cell cycle arrest at G2/M phase, and induce apoptosis in ovarian cancer cells [12, 44]. In addition, genistein treatment also induces autophagic cell death in ovarian cancer cells, which may contribute to its potential to overcome chemoresistance developed from an altered apoptotic signaling pathway . In both platinum-sensitive and platinum-resistant ovarian cancer cells, genistein abrogated NF-κB DNA binding activity and down-regulated anti-apoptotic genes . In addition, genistein suppressed VEGF expression in OVCAR-3 cells . Among six flavonoids, genistein exhibited the most potent inhibitory effect on VEGF expression. Phenoxodiol, a synthetic analog of genistein, also demonstrated a potent inhibitory effect on in vivo angiogenesis . Furthermore, soy isoflavones interfere with production of IL-6, which affects immune homeostasis and inflammatory reactions . Aberrant IL-6 expression has been associated with various pathologic inflammatory conditions, tumor progression, and chemoresistance. Collectively, by modulating inflammatory signaling components including NF-κB, VEGF, and IL-6, genistein may be used as a chemopreventive agent in future clinical trials.
Epigallocatechin-3-gallate (EGCG), a polyphenol constituent of green tea, has shown anti-proliferative and pro-apoptotic effects on several cancer cells, including melanoma, breast cancer, and prostate cancer [43, 64]. The underlying mechanisms include cell cycle arrest, apoptosis induction, stabilization of p53, and inhibition of NF-κB activity [1, 23, 43, 64]. There are limited data on its anti-cancer effects in ovarian cancer cells. EGCG treatment in SKOV-3 cells resulted in inhibition of cell viability and proliferation via induction of apoptosis . In several ovarian cancer cell lines, EGCG exerted its inhibitory effect on cancer cell growth through the induction of apoptosis and cell cycle arrest as well as the regulation of cell cycle-related proteins . The anti-inflammatory effects of EGCG in ovarian cancer need further investigation.
Inflammation has been hypothesized to contribute to ovarian carcinogenesis, and modulation of dysregulated inflammatory pathways has been investigated as a promising chemopreventive strategy against ovarian cancer. In numerous preclinical and clinical studies, phytochemicals have demonstrated anti-cancer effects, largely mediated by regulation of inflammatory pathways. Phytochemicals seem to be suitable candidates for further clinical trials on chemoprevention of various malignancies due to their safety profiles, easy accessibility, and the ability to target multiple signaling pathways involved in carcinogenesis, such as cell proliferation, apoptosis, angiogenesis, and inflammatory signaling pathways. However, there still remain several challenges to researchers, which include the low potency and poor bioavailability of phytochemicals. Curcumin, for example, was detected at low nanomolar levels in the blood of patients who received up to 3.6 g of oral curcumin . Synthetic analogs of natural compounds, such as EF24 for curcumin, may increase their anti-tumor potency and improve bioavailability. In addition, more preclinical and clinical studies are needed to validate the chemopreventive effects of phytochemicals alone or in combination with conventional therapies against ovarian cancer.
This work was supported by the Mid-career Researcher Program through the National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science, and Technology (MEST; No. 2009-0083687) and Priority Research Centers Program through the NRF funded by the MEST (No. 2009-0093820). This research was also supported by the World Class University (WCU) program through the Korea Science and Engineering Foundation, funded by the MEST (R31-2008-000-10056-0).
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