Department of Pharmaceutical and Biological Chemistry, UCL School of Pharmacy, 29-39 Brunswick Square, WC1N 1AX London, UK.
Nat Prod Rep. 2015 Aug;32(8):1170-82. doi: 10.1039/c4np00130c.
Malignant melanoma is the most aggressive form of skin cancer and accounts for about 3% of all cases of malignant tumour. Its incidence is increasing worldwide and it is becoming resistant to current therapeutic agents. Natural products continue to provide lead cytotoxic compounds for cancer treatment but less attention has been given to antimigratory compounds. This paper systematically and critically surveys all natural products with direct in vitro and in vivo pharmacological effects on migration and/or metastasis of melanoma cells and maps the mechanisms of action for these underexploited properties. As a result, over 30 natural active principles are described acting mainly through their antagonistic effects upon the TNF-α and EP2 receptors or the suppression of several protein kinases involved in metastatic pathways such as RAS, PI3K, ERK and FAK. Also, some were able to reduce the level of mesenchymal biomarkers such as N-cadherin and/or elevate the expression of other molecules such as E-cadherin. Consequently, downstream transcription factors namely NF-kB, AP-1, ATF-2, CREB, and HIF were inactivated leading to diminished production of MMPs, IL-1, IL-6, COX-2, VEGF and GM-CSF. This review also discusses the opportunity of combination therapies based on natural products and approved drugs, such as the combination of EGCG and dacarbazine, or the combination of two natural compounds such as quercetin and sulforaphane.
恶性黑素瘤是最具侵袭性的皮肤癌，约占所有恶性肿瘤的 3%。它的发病率在全球范围内呈上升趋势，并且对当前的治疗药物产生了耐药性。天然产物继续为癌症治疗提供先导细胞毒性化合物，但对抗迁移化合物的关注较少。本文系统地和批判性地调查了所有具有直接体外和体内药理作用的天然产物，这些作用是针对黑色素瘤细胞的迁移和/或转移，并绘制了这些未充分利用的特性的作用机制图。结果，描述了 30 多种天然活性物质，它们主要通过拮抗 TNF-α 和 EP2 受体的作用，或抑制几种参与转移途径的蛋白激酶（如 RAS、PI3K、ERK 和 FAK）的作用来发挥作用。此外，一些物质能够降低间充质生物标志物（如 N-钙黏蛋白）的水平，并/或提高其他分子（如 E-钙黏蛋白）的表达。因此，下游转录因子（如 NF-kB、AP-1、ATF-2、CREB 和 HIF）失活，导致 MMPs、IL-1、IL-6、COX-2、VEGF 和 GM-CSF 的产生减少。本文还讨论了基于天然产物和已批准药物的联合治疗的机会，例如 EGCG 和达卡巴嗪的联合治疗，或两种天然化合物如槲皮素和萝卜硫素的联合治疗。
