Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin
Inhibition of skin tumor promotion by TPA using a combination of topically applied ursolic acid and curcumin
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DOI：
10.1002/mc.22918
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发表时间：
2018-10
影响因子：
4.6
通讯作者：
Lisa Tremmel;O. Rho;T. Slaga;J. DiGiovanni
中科院分区：
文献类型：
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作者：
Lisa Tremmel;O. Rho;T. Slaga;J. DiGiovanni
预防仍然是减轻癌症负担的重要策略。预防癌症的一种方法是使用各种组合的植物化学物质作为安全有效的癌症预防剂。本研究的目的是利用小鼠两阶段皮肤癌模型，探讨熊果酸 (UA) 和姜黄素 (Curc) 组合对皮肤肿瘤促进的潜在组合抑制作用。在短期实验中，在 12-O-十四烷酰佛波醇-13-乙酸酯 (TPA) 之前局部给予 UA + Curc 组合可显着抑制表皮 EGFR、p70S6K、NF-κB p50、Src、c-Jun、Rb 和 IκBα 的激活。与 TPA 治疗组相比，联合治疗组的 c-Fos、c-Jun 和 Cox-2 水平也显着降低。通过测量 BrdU 掺入情况评估，UA + Curc 组合对这些信号通路的改变与表皮增殖减少相关。联合用药对表皮炎症基因表达和真皮炎症也有显着影响，其中对 IL-1β、IL-6、IL-22 和 CXCL2 表达的影响最大。此外，皮肤肿瘤实验的结果表明，局部给予 UA + Curc 的组合比单独给予的单个化合物更能显着抑制 TPA 对小鼠皮肤肿瘤的促进作用。尽管组合也进一步降低了肿瘤发生率和多重性，但对无瘤生存、肿瘤大小和肿瘤重量的影响最大。这些结果证明了 UA + Curc 组合的潜在癌症化学预防活性和机制。
Prevention remains an important strategy to reduce the burden of cancer. One approach to prevent cancer is the use of phytochemicals in various combinations as safe and effective cancer preventative agents. The purpose of this study was to examine the effects of the combination of ursolic acid (UA) and curcumin (Curc) for potential combinatorial inhibition of skin tumor promotion using the mouse two‐stage skin carcinogenesis model. In short‐term experiments, the combination of UA + Curc given topically prior to 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) significantly inhibited activation of epidermal EGFR, p70S6K, NF‐κB p50, Src, c‐Jun, Rb, and IκBα. Levels of c‐Fos, c‐Jun, and Cox‐2 were also significantly reduced by the combination compared to the TPA treated group. The alterations in these signaling pathways by the combination of UA + Curc were associated with decreased epidermal proliferation as assessed by measuring BrdU incorporation. Significant effects were also seen with the combination on epidermal inflammatory gene expression and dermal inflammation, with the greatest effects on expression of IL‐1β, IL‐6, IL‐22, and CXCL2. Furthermore, results from skin tumor experiments demonstrated that the combination of UA + Curc given topically significantly inhibited mouse skin tumor promotion by TPA to a greater extent than the individual compounds given alone. The greatest effects were seen on tumor free survival, tumor size, and tumor weight, although tumor incidence and multiplicity were also further reduced by the combination. These results demonstrate the potential cancer chemopreventive activity and mechanism(s) for the combination of UA + Curc.