姜黄素通过靶向核因子-κB通路抑制卵巢癌的肿瘤生长和血管生成。

Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway.

作者信息

Lin Yvonne G, Kunnumakkara Ajaikumar B, Nair Asha, Merritt William M, Han Liz Y, Armaiz-Pena Guillermo N, Kamat Aparna A, Spannuth Whitney A, Gershenson David M, Lutgendorf Susan K, Aggarwal Bharat B, Sood Anil K

机构信息

Department of Gynecologic Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

出版信息

Clin Cancer Res. 2007 Jun 1;13(11):3423-30. doi: 10.1158/1078-0432.CCR-06-3072.

DOI:10.1158/1078-0432.CCR-06-3072

PMID:17545551

Abstract

PURPOSE

Curcumin, a component of turmeric, has been shown to suppress inflammation and angiogenesis largely by inhibiting the transcription factor nuclear factor-kappaB (NF-kappaB). This study evaluates the effects of curcumin on ovarian cancer growth using an orthotopic murine model of ovarian cancer.

EXPERIMENTAL DESIGN

In vitro and in vivo experiments of curcumin with and without docetaxel were done using human ovarian cancer cell lines SKOV3ip1, HeyA8, and HeyA8-MDR in athymic mice. NF-kappaB modulation was ascertained using electrophoretic mobility shift assay. Evaluation of angiogenic cytokines, cellular proliferation (proliferating cell nuclear antigen), angiogenesis (CD31), and apoptosis (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) was done using immunohistochemical analyses.

RESULTS

Curcumin inhibited inducible NF-kappaB activation and suppressed proliferation in vitro. In vivo dose-finding experiments revealed that 500 mg/kg orally was the optimal dose needed to suppress NF-kappaB and signal transducers and activators of transcription 3 activation and decrease angiogenic cytokine expression. In the SKOV3ip1 and HeyA8 in vivo models, curcumin alone resulted in 49% (P = 0.08) and 55% (P = 0.01) reductions in mean tumor growth compared with controls, whereas when combined with docetaxel elicited 96% (P < 0.001) and 77% reductions in mean tumor growth compared with controls. In mice with multidrug-resistant HeyA8-MDR tumors, treatment with curcumin alone and combined with docetaxel resulted in significant 47% and 58% reductions in tumor growth, respectively (P = 0.05). In SKOV3ip1 and HeyA8 tumors, curcumin alone and with docetaxel decreased both proliferation (P < 0.001) and microvessel density (P < 0.001) and increased tumor cell apoptosis (P < 0.05).

CONCLUSIONS

Based on significant efficacy in preclinical models, curcumin-based therapies may be attractive in patients with ovarian carcinoma.

摘要

目的

姜黄素是姜黄的一种成分，已被证明主要通过抑制转录因子核因子-κB（NF-κB）来抑制炎症和血管生成。本研究使用卵巢癌原位小鼠模型评估姜黄素对卵巢癌生长的影响。

实验设计

在无胸腺小鼠中，使用人卵巢癌细胞系SKOV3ip1、HeyA8和HeyA8-MDR对含或不含多西他赛的姜黄素进行体外和体内实验。使用电泳迁移率变动分析确定NF-κB调节情况。使用免疫组织化学分析评估血管生成细胞因子、细胞增殖（增殖细胞核抗原）、血管生成（CD31）和细胞凋亡（末端脱氧核苷酸转移酶介导的dUTP缺口末端标记）。

结果

姜黄素在体外抑制诱导性NF-κB激活并抑制增殖。体内剂量探索实验表明，口服500mg/kg是抑制NF-κB以及信号转导和转录激活因子3激活并降低血管生成细胞因子表达所需的最佳剂量。在SKOV3ip1和HeyA8体内模型中，与对照组相比，单独使用姜黄素导致平均肿瘤生长分别减少49%（P = 0.08）和55%（P = 0.01），而与多西他赛联合使用时，与对照组相比，平均肿瘤生长分别减少96%（P < 0.001）和77%。在患有多药耐药性HeyA8-MDR肿瘤的小鼠中，单独使用姜黄素和与多西他赛联合治疗分别使肿瘤生长显著减少47%和58%（P = 0.05）。在SKOV3ip1和HeyA8肿瘤中，单独使用姜黄素以及与多西他赛联合使用均降低了增殖（P < 0.001）和微血管密度（P < 0.001），并增加了肿瘤细胞凋亡（P < 0.05）。