Department of Biochemistry, McGill University, Montreal, Québec, H3G 1Y6, Canada.
Department of Medicine, McGill University, Montreal, Québec, H3G 1Y6, Canada.
Sci Rep. 2019 Feb 4;9(1):1265. doi: 10.1038/s41598-018-37666-5.
Translation is a highly regulated process that is perturbed in human cancers, often through activation of the PI3K/mTOR pathway which impacts directly on the ribosome recruitment phase of translation initiation. While significant research has focused on "drugging" components of the PI3K/mTOR network, efforts have also been directed towards inhibiting eukaryotic initiation factor (eIF) 4F-dependent translation. Small molecule inhibitors of this complex have been identified, characterized, and used to validate the rationale of targeting this step to curtail tumor cell growth and modulate chemotherapy response. One such class of compounds are the rocaglates, secondary metabolites from the plant genus Aglaia, which target the RNA helicase subunit of eIF4F, eIF4A. Here we explore the ability of synthetic derivatives of aglaiastatins and an aglaroxin derivative to target the translation process in vitro and in vivo and find the synthetic derivative oxo-aglaiastatin to possess such activity. Oxo-aglaiastatin inhibited translation in vitro and in vivo and synergized with doxorubicin, ABT-199 (a Bcl-2 antagonist), and dexamethasone when tested on hematological cancer cells. The biological activity of oxo-aglaiastatin was shown to be a consequence of inhibiting eIF4A1 activity.
翻译是一个受到高度调控的过程，在人类癌症中经常受到干扰，通常是通过激活 PI3K/mTOR 途径来实现，该途径直接影响翻译起始的核糖体募集阶段。尽管大量研究集中在“靶向”PI3K/mTOR 网络的成分上，但也有人努力抑制真核起始因子 (eIF) 4F 依赖性翻译。已经鉴定、表征了这种复合物的小分子抑制剂，并用于验证靶向这一步骤以遏制肿瘤细胞生长和调节化疗反应的原理。rocaglates 是一类来自植物属 Aglaia 的次生代谢产物，就是其中的一种化合物，它靶向 eIF4F 的 RNA 解旋酶亚基 eIF4A。在这里，我们研究了 aglaiastatin 的合成衍生物和 aglaroxin 衍生物在体外和体内靶向翻译过程的能力，并发现合成衍生物 oxo-aglaiastatin 具有这种活性。Oxo-aglaiastatin 在体外和体内均抑制翻译，并在血液癌细胞上与多柔比星、ABT-199（一种 Bcl-2 拮抗剂）和地塞米松联合使用时具有协同作用。Oxo-aglaiastatin 的生物学活性是抑制 eIF4A1 活性的结果。
