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

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.

Antimetastatic Therapies of the Polysulfide Diallyl Trisulfide against Triple-Negative Breast Cancer (TNBC) via Suppressing MMP2/9 by Blocking NF-κB and ERK/MAPK Signaling Pathways.

BACKGROUND: Migration and invasion are two crucial steps of tumor metastasis. Blockage of these steps may be an effective strategy to reduce the risk. The objective of the present study was to investigate the effects of diallyl trisulfide (DATS), a natural organosulfuric compound with most sulfur atoms found in garlic, on migration and invasion in triple negative breast cancer (TNBC) cells. Molecular mechanisms underlying the anticancer effects of DATS were further investigated. METHODS AND RESULTS: MDA-MB-231 cells and HS 578t breast cancer cells were treated with different concentrations of DATS. DATS obviously suppressed the migration and invasion of two cell lines and changed the morphological. Moreover, DATS inhibited the mRNA/protein/ enzymes activities of MMP2/9 via attenuating the NF-κB pathway. DATS also inhibited ERK/MAPK rather than p38 and JNK. CONCLUSION: DATS inhibits MMP2/9 activity and the metastasis of TNBC cells, and emerges as a potential anti-cancer agent. The inhibitory effects are associated with down-regulation of the transcriptional activities of NF-κB and ERK/MAPK signaling pathways.