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Apoptosis-independent organoruthenium anticancer complexes that overcome multidrug resistance: self-assembly and

Mun Juinn Chow1, Mohammad Alfiean2, Giorgia Pastorin3,4

  • 1Department of Chemistry , National University of Singapore , 3 Science Drive 3 , 117543 Singapore .

Chemical Science
|August 30, 2018
PubMed

Insights

New organoruthenium anticancer agents were identified using a novel assembly and screening strategy. These agents induce apoptosis-independent cell death, offering a promising alternative for treating multidrug-resistant cancers.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Drug Discovery

Background:

  • Multidrug resistance (MDR) significantly hinders chemotherapy efficacy against cancer.
  • Developing novel anticancer agents that bypass MDR by inducing apoptosis-independent programmed cell death is crucial.
  • The complex and poorly understood pathways of alternative cell death pose challenges for traditional target-based drug discovery.

Purpose of the Study:

  • To establish a coordination-directed three-component assembly and phenotypic screening strategy for identifying novel organoruthenium anticancer agents.
  • To discover drug candidates that induce apoptosis-independent programmed cell death, thereby circumventing MDR.
  • To validate the mechanism of action and efficacy of identified compounds in both apoptosis-sensitive and -resistant cancer models.

Main Methods:

  • On-plate synthesis and high-throughput screening of 195 organoruthenium complexes against various cancer cell lines, including MDR phenotypes.
  • Phenotypic screening focused on identifying compounds that induce cell death independently of apoptosis.
  • Validation assays included assessment of apoptotic biomarkers, caspase activity, and efficacy in apoptosis-sensitive versus -resistant colorectal cancer models.

Main Results:

  • A novel coordination-directed assembly and phenotypic screening approach successfully identified potential anticancer agents.
  • Two organoruthenium complexes demonstrated significant anticancer activity through an apoptosis-independent mechanism.
  • The identified compounds exhibited caspase-independent activity and were equally effective in both apoptosis-sensitive and -resistant colorectal cancer cells, lacking induction of apoptotic biomarkers.

Conclusions:

  • The developed strategy offers a viable alternative for discovering anticancer agents that bypass multidrug resistance.
  • The identified organoruthenium compounds represent promising candidates for treating refractory cancer phenotypes due to their apoptosis-independent mode of action.
  • This research opens new avenues for developing chemotherapy alternatives for patients with limited treatment options.

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