Synthetic lethality theory approaches to effective substance discovery and functional mechanisms elucidation of anti-cancer phytomedicine,Phytomedicine

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Synthetic lethality theory approaches to effective substance discovery and functional mechanisms elucidation of anti-cancer phytomedicine
Phytomedicine ( IF 6.7 ) Pub Date : 2021-08-20 , DOI: 10.1016/j.phymed.2021.153718
Yunlong Shan ₁ , Fang Wang ₂ , Zhonghong Wei ₃ , Yin Lu ₃

Affiliation

Background

Longstanding, successful use of combinations of phytopharmaceuticals in traditional Chinese medicine (TCM) has caught the attention of several pharmacologists to natural medicines. However, the development and popularisation of TCM is mainly limited because of the unavailability of reports clarifying the mechanisms of action and pharmacologically active ingredients in such formulations. Previous studies on natural medicines have mostly focused on their dominant components using forward pharmacology which often neglects trace components. It is necessary to asess the pharmacological and therapeutic superiority of many such trace components in comparison with single constituents.

Purpose

In this study, we aimed to propose a new pharmacological research strategy for TCM. In particular, we presented the possibility that the effective mechanism of action of trace components of TCM is based on synthetic lethality. We sincerely hope to explore this theory further.

Method

We obtained retrieve published research information related to synthetic lethality, phytochemicals and Chinese medicine from PubMed and Google scholar. Based on the inclusion criteria, 71 studies were selected and discussed in this review.

Results

As an interaction among genes, synthetic lethality can amplify co-regulatory biological effects exponentially. Synthetic strategies have been successfully applied for research and development of anti-tumour agents, including poly ADP-ribose polymerase inhibitors and clinical combination of chemotherapeutic agents for efficacy enhancement and toxicity reduction. TCM drugs contain several secondary metabolites to combat environmental stresses, providing a multi-component basis for corresponding synergistic targets. Therefore, we aimed to study whether this method could be used to identify active components present in trace amounts in TCM drugs. Based on a reverse concept of target–component–effect and identified synergistic targets, we explored the mechanisms of action of weakly active components present in trace amounts in TCM drugs to assess combinations of potential synergistic components.

Conclusion

This pattern of synthetic lethality not only elucidated the mechanisms of action of TCM drugs from a new perspective but also inspired future studies on discovering naturally occurring active components.

中文翻译：

合成致死理论的有效物质发现方法和抗癌植物药的功能机制阐明

背景

植物药物组合在传统中药 (TCM) 中的长期成功使用引起了几位药理学家对天然药物的关注。然而，中医药的发展和普及主要是因为缺乏阐明此类剂型的作用机制和药理活性成分的报告。以前对天然药物的研究主要集中在使用正向药理学的主要成分上，而这往往忽略了微量成分。有必要评估许多此类微量成分与单一成分相比的药理学和治疗优势。

目的

在这项研究中，我们旨在提出一种新的中药药理研究策略。特别是，我们提出了中药微量成分的有效作用机制基于合成致死率的可能性。我们真诚地希望进一步探索这一理论。

方法

我们从 PubMed 和 Google 学者处检索了与合成致死率、植物化学物质和中药相关的已发表研究信息。根据纳入标准，本综述选择并讨论了 71 项研究。

结果

作为基因之间的相互作用，合成致死率可以成倍地放大协同调节生物效应。合成策略已成功应用于抗肿瘤药物的研究和开发，包括聚 ADP-核糖聚合酶抑制剂和用于增强疗效和降低毒性的化疗药物的临床组合。中药药物含有多种次生代谢物来对抗环境压力，为相应的协同目标提供了多组分基础。因此，我们旨在研究该方法是否可用于鉴定中药中痕量存在的活性成分。基于目标-成分-效应的反向概念和确定的协同目标，