School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan; Women's Health Research Laboratory, Changhua Christian Hospital, Changhua, Taiwan.
Cancer Research Center, Changhua Christian Hospital, Changhua, Taiwan; Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
Phytomedicine. 2019 Sep;62:152964. doi: 10.1016/j.phymed.2019.152964. Epub 2019 May 18.
Phloretin, a dihydrochalcone flavonoid, possesses anti-inflammatory activity and inhibits the growth of various cancers. However, the flavonoid's effect on cervical cancer metastasis and angiogenesis remains unknown.
In this study, we provide molecular evidence associated with the antimetastatic and antiangiogenic effects of phloretin.
In this study, the anti-invasive effect of phloretin (0-60 μM) in cervical cancer cells was evaluated using the Matrigel invasion assay, gelatin zymography, cell-matrix adhesion assay, wound healing assay, and Western blotting. Antiangiogenic potential of phloretin (0-100 μM) was assessed by the Matrigel tube formation assay. The in vivo antitumor effect of phloretin (10 or 20 mg/kg) was fed by oral gavage and determined using subcutaneous inoculation and tail vein injection in immunodeficient nude mice.
Phloretin (60 μM) showed marked suppression of invasion and migration through downregulation of matrix metalloproteinase (MMP)-2, MMP-3, and cathepsin S in human SiHa cervical cancer cells. Phloretin (60 μM) reversed the epithelial-mesenchymal transition induced by transforming growth factor-β1 and downregulated mesenchymal markers, such as fibronectin, vimentin, and RhoA. Phloretin (100 μM) treatment significantly inhibited the aldehyde dehydrogenase 1 activity of SiHa cells, reduced the self-renewal properties and stemness signatures of CD44 and Sox-2 in sphere-forming cervical cancer-derived tumor-initiating cells, and inhibited the invasion, MMP-2 activity, and tube formation capacity of human umbilical vein endothelial cells. The ability of phloretin (20 mg/kg) to suppress lung metastasis and tumor growth in SiHa cells was evidenced by tail vein injection and subcutaneous inoculation in a tumor xenograft model.
In summary, the findings indicate that phloretin inhibits the metastatic and angiogenic abilities and cancer stemness of SiHa cells, thereby suggesting that this flavonoid is a promising therapeutic agent for the treatment of human cervical cancer cells.
根皮苷是一种二氢查尔酮类黄酮，具有抗炎活性，并能抑制多种癌症的生长。然而，这种类黄酮对宫颈癌转移和血管生成的影响尚不清楚。
本研究提供了与根皮苷的抗转移和抗血管生成作用相关的分子证据。
在这项研究中，我们使用 Matrigel 侵袭实验、明胶酶谱分析、细胞-基质黏附实验、划痕愈合实验和 Western blot 分析评估了根皮苷（0-60 μM）对宫颈癌细胞的抗侵袭作用。通过 Matrigel 管形成实验评估了根皮苷（0-100 μM）的抗血管生成潜力。通过口服灌胃给予根皮苷（10 或 20 mg/kg），并在免疫缺陷裸鼠中通过皮下接种和尾静脉注射来测定其体内抗肿瘤作用。
根皮苷（60 μM）显著抑制人 SiHa 宫颈癌细胞的侵袭和迁移，下调基质金属蛋白酶（MMP）-2、MMP-3 和组织蛋白酶 S。根皮苷（60 μM）逆转转化生长因子-β1 诱导的上皮-间充质转化，并下调间充质标志物，如纤连蛋白、波形蛋白和 RhoA。根皮苷（100 μM）处理显著抑制 SiHa 细胞醛脱氢酶 1 的活性，降低 CD44 和 Sox-2 在球体形成宫颈癌起始肿瘤细胞中的自我更新特性和干细胞特征，并抑制人脐静脉内皮细胞的侵袭、MMP-2 活性和管形成能力。根皮苷（20 mg/kg）通过尾静脉注射和皮下接种在肿瘤异种移植模型中抑制 SiHa 细胞的肺转移和肿瘤生长的能力得到了证实。
综上所述，研究结果表明，根皮苷抑制 SiHa 细胞的转移和血管生成能力及癌症干性，表明该黄酮类化合物有望成为治疗人宫颈癌的治疗剂。
