Bacterial Cytological Profiling Reveals the Mechanism of Action of Anticancer Metal Complexes

Yang Sun, David K. Heidary, Zhihui Zhang, Christopher I. Richards, Edith C. Glazer

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Target identification and mechanistic studies of cytotoxic agents are challenging processes that are both time-consuming and costly. Here we describe an approach to mechanism of action studies for potential anticancer compounds by utilizing the simple prokaryotic system, E. coli, and we demonstrate its utility with the characterization of a ruthenium polypyridyl complex [Ru(bpy) 2 dmbpy 2+ ]. Expression of the photoconvertible fluorescent protein Dendra2 facilitated both high throughput studies and single-cell imaging. This allowed for simultaneous ratiometric analysis of inhibition of protein production and phenotypic investigations. The profile of protein production, filament size and population, and nucleoid morphology revealed important differences between inorganic agents that damage DNA vs more selective inhibitors of transcription and translation. Trace metal analysis demonstrated that DNA is the preferred nucleic acid target of the ruthenium complex, but further studies in human cancer cells revealed altered cell signaling pathways compared to the commonly administrated anticancer agent cisplatin. This study demonstrates E. coli can be used to rapidly distinguish between compounds with disparate mechanisms of action and also for more subtle distinctions within in studies in mammalian cells.

Original languageEnglish
Pages (from-to)3404-3416
Number of pages13
JournalMolecular Pharmaceutics
Volume15
Issue number8
DOIs
StatePublished - Aug 6 2018

Bibliographical note

Publisher Copyright:
© 2018 American Chemical Society.

Keywords

  • bacterial cytological profiling
  • cancer
  • cisplatin
  • drug discovery
  • ruthenium

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery

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