Chen Sophie S, Michael Agnieszka, Butler-Manuel Simon A
Department of Research and Development, Ovarian and Prostate Cancer Research Trust Laboratory, Guildford, Surrey, United Kingdom.
Discov Med. 2012 Jan;13(68):7-17.
Epithelial ovarian cancer (EOC) is the leading cause of death among gynecological malignancies worldwide. The five-year survival rates for stage IIIC and IV patients are 29% and 13%, respectively. Type-2 EOC cells have been found to be associated with this late stage disease. In contrast, women diagnosed in stage 1 disease, which mostly exhibits type-1 cells, have a high 5-year survival rate (90%). Recent progress in understanding the pathogenesis of EOC and inflammatory signaling pathways revealed that type-2 cells frequently express a deleted or mutated TP53 (60-80%), or aberrations in BRCA1 (30-60%) and BRCA2 (15-30%). The deletion or mutation of TP53 results in a dysregulated inflammatory signal network and contributes to an immunosuppressive microenvironment. Thus, to be effective, EOC therapy may be necessary to cover two areas: (1) direct cytotoxic killing of cancer cells; (2) reversion of the immunosuppressive microenvironment. Presently the first strategy is advancing rapidly while the second strategy remains behind. Isolation and characterization of cancer stem cells (CSCs) have helped to confirm the dynamic role of the tumor microenvironment in promoting cancer metastasis and recurrence. Based on widely published in vitro and mouse-model data, some anti-inflammatory phytochemicals appear to exhibit activity in modulating the tumor microenvironment. Specifically, apiegenin, baicalein, curcumin, EGCG, genistein, luteolin, oridonin, quercetin, and wogonin repress NF-kappaB (NF-κB, a proinflammatory transcription factor) and inhibit proinflammatory cytokines such as TNF-α and IL-6. Additionally, most of these phytochemicals have been shown to stabilize p53 protein, sensitize TRAIL (TNF receptor apoptosis-inducing ligand) induced apoptosis, and prevent or delay chemotherapy-resistance. Recent studies further indicate that apigenin, genistein, kaempferol, luteolin, and quercetin potently inhibit VEGF production and suppress ovarian cancer cell metastasis in vitro. Lastly, oridonin and wogonin were suggested to suppress ovarian CSCs as is reflected by down-regulation of the surface marker EpCAM. Unlike NSAIDS (non-steroid anti-inflammatory drugs), well documented clinical data for phyto-active compounds are lacking. In order to evaluate objectively the potential benefit of these compounds in the treatment of ovarian cancer, strategically designed, large scale studies are warranted.
上皮性卵巢癌（EOC）是全球妇科恶性肿瘤死亡的主要原因。IIIC期和IV期患者的五年生存率分别为29%和13%。已发现2型EOC细胞与这种晚期疾病相关。相比之下，诊断为I期疾病（大多表现为1型细胞）的女性5年生存率较高（90%）。在了解EOC发病机制和炎症信号通路方面的最新进展表明，2型细胞经常表达缺失或突变的TP53（60 - 80%），或BRCA1（30 - 60%）和BRCA2（15 - 30%）存在畸变。TP53的缺失或突变导致炎症信号网络失调，并促成免疫抑制微环境。因此，为了有效，EOC治疗可能需要涵盖两个方面：（1）直接对癌细胞进行细胞毒性杀伤；（2）逆转免疫抑制微环境。目前第一种策略进展迅速，而第二种策略仍相对滞后。癌症干细胞（CSC）的分离和表征有助于证实肿瘤微环境在促进癌症转移和复发中的动态作用。基于广泛发表的体外和小鼠模型数据，一些抗炎植物化学物质似乎在调节肿瘤微环境方面具有活性。具体而言，芹菜素、黄芩素、姜黄素、表没食子儿茶素没食子酸酯（EGCG）、染料木黄酮、木犀草素、冬凌草甲素、槲皮素和汉黄芩素可抑制核因子κB（NF-κB，一种促炎转录因子）并抑制促炎细胞因子如肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）。此外，这些植物化学物质中的大多数已被证明可稳定p53蛋白，使肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡敏感化，并预防或延迟化疗耐药性。最近的研究进一步表明，芹菜素、染料木黄酮、山奈酚、木犀草素和槲皮素在体外可有效抑制血管内皮生长因子（VEGF）的产生并抑制卵巢癌细胞转移。最后，冬凌草甲素和汉黄芩素被认为可抑制卵巢CSC，这可通过表面标志物上皮细胞黏附分子（EpCAM）的下调反映出来。与非甾体抗炎药（NSAIDS）不同，植物活性化合物缺乏充分记录的临床数据。为了客观评估这些化合物在治疗卵巢癌中的潜在益处，有必要进行精心设计的大规模研究。
