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

Abstract

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 assess 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.

Keywords: Environmental stress; Medicinal plants; Reverse pharmacology; Synthetic lethality; Trace component; Traditional Chinese medicine.