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Gold nanoparticles loaded with cullin-5 DNA increase sensitivity to 17-AAG in cullin-5 deficient breast cancer cells

Sarah Talamantez-Lyburn1, Pierce Brown2, Nicole Hondrogiannis2

  • 1Department of Biological Sciences, Towson University, Towson, MD, United States.

International Journal of Pharmaceutics
|April 19, 2019
PubMed

Insights

Gold nanoparticles deliver Heat Shock Protein 90 (HSP90) inhibitor 17-AAG and Cullin-5 (Cul5) DNA to cancer cells. This combination therapy overcomes drug resistance in Cul5-deficient breast cancer cells.

Area of Science:

  • Oncology
  • Nanotechnology
  • Molecular Biology

Background:

  • Heat Shock Protein 90 (HSP90) inhibitors show promise for cancer treatment due to tumor cell dependence on HSP90.
  • Cullin-5 (Cul5) E3 ubiquitin ligase is crucial for HSP90 inhibitor efficacy, but its low expression in breast cancer may limit treatment success.
  • The decreased efficacy of HSP90 inhibitors like 17-AAG as monotherapy in some breast cancers is potentially linked to low Cul5 levels.

Purpose of the Study:

  • To investigate the role of Cullin-5 (Cul5) expression in breast cancer's response to HSP90 inhibitors.
  • To develop a novel drug delivery system using gold nanoparticles (AuNPs) for combined delivery of 17-AAG and Cul5 DNA.
  • To evaluate the efficacy of this combined delivery system in sensitizing Cul5-deficient breast cancer cells to 17-AAG.

Main Methods:

  • Gold nanoparticles (AuNPs) were synthesized and characterized using UV-vis spectroscopy, Transmission Electron Microscopy (TEM), gel electrophoresis, and 1H NMR.
  • AuNPs were loaded with both the HSP90 inhibitor 17-AAG and Cul5 DNA.
  • Cul5-deficient AU565 breast cancer cells were treated with AuNPs carrying 17-AAG and Cul5 DNA, and cytotoxicity was assessed.

Main Results:

  • Characterization confirmed successful attachment of 17-AAG and DNA to AuNPs, along with AuNP stability.
  • Delivery of AuNPs containing Cul5 DNA significantly increased the sensitivity of Cul5-deficient AU565 cells to 17-AAG.
  • Combined delivery of Cul5 DNA and 17-AAG via AuNPs resulted in enhanced cytotoxicity in AU565 cells.

Conclusions:

  • Low Cullin-5 (Cul5) expression may contribute to resistance against HSP90 inhibitors in breast cancer.
  • Gold nanoparticle-mediated co-delivery of Cul5 DNA and 17-AAG is a viable strategy to enhance anti-cancer efficacy.
  • This approach offers a potential method to sensitize drug-resistant tumor cells, improving therapeutic outcomes for HSP90 inhibitor treatments.
Keywords:
17-AAGCancerChemotherapyCullin 5Gold nanoparticleHsp90Ubiquitin ligase

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