粗糠柴毒素的非经典抗癌活性研究进展

Study Progress of Non-Conventional Anticancer Activity of Rottlerin

癌症作为当今世界一个主要的公共卫生问题,其难以被治愈的情况一直未得到有效的解决。粗糠柴毒素(Rottlerin)是一种从大戟科植物中提取出来的天然化合产物,具有多种抗癌生物活性。近些年来的研究已充分证明Rottlerin作为多种激酶、转录因子和信号分子的抑制剂,可控制癌症细胞的存活或死亡。虽然Rottlerin的抗癌活性一直被认为是调控细胞凋亡或自噬,然而最近的研究揭示了其毒性机制的存在。本综述主要介绍Rottlerin能够直接结合和抑制某些关键分子,例如细胞外调节蛋白激酶(ERK)和哺乳动物雷帕霉素靶蛋白(mTOR),从而独立于上游信号,并通过mTORC1(哺乳动物雷帕霉素靶蛋白复合体1)/4EBP-1(真核翻译起始因子4E结合蛋白1)/eIF4E(真核翻译起始因子4E)轴负调控蛋白质的翻译起始阶段,并抑制内质网应激负调控的真核翻译起始因子2(eIF2)的表达。这些全新的机制,已被证实可诱导乳腺癌和皮肤癌细胞系的死亡,极大增加Rottlerin作为开发新型治疗药物的天然先导化合物的潜力。

As a major public health problem in the world today,the difficulty of curing cancer has not been effectively solved.Rottlerin is a natural chemical product extracted from plants in the Euphorbiaceae family with a variety of anti-cancer biological activities.Recent studies have demonstrated that Rottlerin controls the survival or death of cancer cells as an inhibitor of a variety of kinases,transcription factors,and signaling molecules.While the anticancer activity of Rottlerin has been thought to regulate apoptosis or autophagy,recent studies have revealed the presence of other toxic mechanisms.This review mainly introduces the ability of Rottlerin to directly bind and inhibit certain key molecules,such as extracellular regulated protein kinases(ERK)and mammalian target of rapamycin(mTOR),thus independent of upstream signals,negatively regulate the translation initiation stage of proteins through the mTORC1(mTOR complex 1)/4EBP1(eukaryotic translation initiation factor 4E-binding protein 1)/eIF4E(eukaryotic translation initiation factor 4E)axis,as well inhibit the expression of the translation initiation factor eukaryotic translation initiation factor 2(eIF2),which is negatively regulated by endoplasmic reticulum stress.These novel mechanisms,which have been shown to induce death in breast cancer and skin cancer cell lines,greatly increase the potential of Rottlerin as a natural lead compound for the development of novel therapeutics.