Siddiqui Rafat A, Harvey Kevin A, Walker Candace, Altenburg Jeffrey, Xu Zhidong, Terry Colin, Camarillo Ignacio, Jones-Hall Yava, Mariash Cary
Cellular Biochemistry Laboratory, Indiana University Health, Indianapolis, IN 46202, USA.
BMC Cancer. 2013 Sep 13;13:418. doi: 10.1186/1471-2407-13-418.
The major obstacles to the successful use of individual nutritional compounds as preventive or therapeutic agents are their efficacy and bioavailability. One approach to overcoming this problem is to use combinations of nutrients to induce synergistic effects. The objective of this research was to investigate the synergistic effects of two dietary components: docosahexaenoic acid (DHA), an omega-3 fatty acid present in cold-water fish, and curcumin (CCM), an herbal nutrient present in turmeric, in an in vivo model of DMBA-induced mammary tumorigenesis in mice.
We used the carcinogen DMBA to induce breast tumors in SENCAR mice on control, CCM, DHA, or DHA + CCM diets. Appearance and tumor progression were monitored daily. The tumors were harvested 15 days following their first appearance for morphological and immunohistological analysis. Western analysis was performed to determine expression of maspin and survivin in the tumor tissues. Characterization of tumor growth was analyzed using appropriate statistical methods. Otherwise all other results are reported as mean ± SD and analyzed with one-way ANOVA and Tukey's post hoc procedure.
Analysis of gene microarray data indicates that combined treatment with DHA + CCM altered the profile of "PAM50" genes in the SK-BR-3 cell line from an ER⁻/Her-2⁺ to that resembling a "normal-like" phenotype. The in vivo studies demonstrated that DHA + CCM treatment reduced the incidence of breast tumors, delayed tumor initiation, and reduced progression of tumor growth. Dietary treatment had no effect on breast size development, but tumors from mice on a control diet (untreated) were less differentiated than tumors from mice fed CCM or DHA + CCM diets. The synergistic effects also led to increased expression of the pro-apoptotic protein, maspin, but reduced expression of the anti-apoptotic protein, survivin.
The SK-BR-3 cells and DMBA-induced tumors, both with an ER⁻ and Her-2⁺ phenotype, were affected by the synergistic interaction of DHA and CCM. This suggests that the specific breast cancer phenotype is an important factor for predicting efficacy of these nutraceuticals. The combination of DHA and CCM is potentially a dietary supplemental treatment for some breast cancers, likely dependent upon the molecular phenotype of the cancer.
将单一营养化合物成功用作预防或治疗药物的主要障碍是其功效和生物利用度。克服这一问题的一种方法是使用营养物质组合来诱导协同效应。本研究的目的是在二甲基苯并蒽（DMBA）诱导的小鼠乳腺肿瘤发生的体内模型中，研究两种膳食成分的协同效应：二十二碳六烯酸（DHA），一种存在于冷水鱼中的ω-3脂肪酸，以及姜黄素（CCM），一种存在于姜黄中的草本营养物质。
我们使用致癌物DMBA在喂食对照、CCM、DHA或DHA+CCM饮食的SENCAR小鼠中诱导乳腺肿瘤。每天监测肿瘤的出现和进展。肿瘤首次出现后15天收获肿瘤，进行形态学和免疫组织学分析。进行蛋白质免疫印迹分析以确定肿瘤组织中maspin和生存素的表达。使用适当的统计方法分析肿瘤生长特征。否则，所有其他结果均以平均值±标准差报告，并采用单因素方差分析和Tukey事后检验程序进行分析。
基因微阵列数据分析表明，DHA+CCM联合处理使SK-BR-3细胞系中“PAM50”基因的谱从ER⁻/Her-2⁺改变为类似“正常样”表型。体内研究表明，DHA+CCM处理降低了乳腺肿瘤的发生率，延迟了肿瘤起始，并减缓了肿瘤生长进程。饮食处理对乳腺大小发育没有影响，但对照饮食（未处理）小鼠的肿瘤比喂食CCM或DHA+CCM饮食小鼠的肿瘤分化程度低。协同效应还导致促凋亡蛋白maspin的表达增加，但抗凋亡蛋白生存素的表达降低。
具有ER⁻和Her-2⁺表型的SK-BR-3细胞和DMBA诱导的肿瘤受到DHA和CCM协同相互作用的影响。这表明特定的乳腺癌表型是预测这些营养保健品功效的重要因素。DHA和CCM的组合可能是某些乳腺癌的膳食补充治疗方法，这可能取决于癌症的分子表型。
