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Molecular networking as a dereplication strategy for monitoring metabolites of natural product treated cancer cells.

RATIONALE
Natural products have been great sources for drug discovery. However, the structures of natural products are diverse and hard to be elucidated. Cordyceps militaris is a parasitic fungus which usually grows on the host insects. The metabolites of C. militaris have been reported to act as chemotherapeutic agents. In this study, we aimed for the structural elucidation of specialized metabolites derived from C. militaris, and its metabolic impact in the leukemia cells.


METHODS
We described a liquid chromatography data-dependent mass spectrometric platform combining tandem mass analysis and molecular networking. Leukemia cells that treated with C. militaris extract and the control groups were visualized their metabolic profiles by using GNPS. By this method, we were able to elucidate structures of metabolites from medicinal fungus extracts and cancer cells then to recognize their changes in a semi-quantitative manner.


RESULTS
Using C. militaris and leukemia cells as demonstrations, we found that approximately a hundred of new ion species were present in the treated leukemia cells, suggesting a highly altered metabolic profile. In specific, basing on the tandem mass spectral similarity, we proposed that cordycepin, a key fungus-derived therapeutic agent known for its anti-tumor capability, was transformed into its methylthio form in leukemia cells.


CONCLUSIONS
In conclusion, this platform provides an ability to investigate complex molecular interactions of natural products in mammalian cells. By incorporating tandem mass spectrometry and molecular networking, we were able to reveal the chemical modification of crude bioactive compounds. For example, the potential bioactive compounds which might be modified from cordycepin. We envision that such mass spectrometry-based workflow, combining with other metabolomics platforms, would enable much wider applicability to cell biology and be of great potential to pharmacological study as well as drug discovery.