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Gold nanoparticle conjugated Rad6 inhibitor induces cell death in triple negative breast cancer cells by inducing
Brittany Haynes1, Yanhua Zhang2, Fangchao Liu2
1Karmanos Cancer Institute, Detroit, MI, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
Abstract:
We recently developed a small molecule inhibitor SMI#9 for Rad6, a protein overexpressed in aggressive breast cancers and involved in DNA damage tolerance. SMI#9 induces cytotoxicity in cancerous cells but spares normal breast cells; however, its therapeutic efficacy is limited by poor solubility. Here we chemically modified SMI#9 to enable its conjugation and hydrolysis from gold nanoparticle (GNP). SMI#9-GNP and parent SMI#9 activities were compared in mesenchymal and basal triple negative breast cancer (TNBC) subtype cells. Whereas SMI#9 is cytotoxic to all TNBC cells, SMI#9-GNP is endocytosed and cytotoxic only in mesenchymal TNBC cells. SMI#9-GNP endocytosis in basal TNBCs is compromised by aggregation. However, when combined with cisplatin, SMI#9-GNP is imported and synergistically increases cisplatin sensitivity. Like SMI#9, SMI#9-GNP spares normal breast cells. The released SMI#9 is active and induces cell death via mitochondrial dysfunction and PARP-1 stabilization/hyperactivation. This work signifies the development of a nanotechnology-based Rad6-targeting therapy for TNBCs.
From The Clinical Editor:
Protein Rad6 is overexpressed in breast cancer cells and its blockade may provide a new treatment against 3N breast cancer. The authors conjugated a small molecule inhibitor SMI#9 for Rad6 to gold nanoparticles in this study and showed that this new formulation specifically targeted chemo-resistant breast cancer cells and highlighted the importance of nanotechnology in drug carrier development.
Insights
A novel gold nanoparticle (GNP) drug delivery system for SMI#9, a Rad6 inhibitor, shows promise for treating triple-negative breast cancer (TNBC). This nanotechnology approach enhances targeted delivery and overcomes solubility issues, offering a new therapeutic strategy for aggressive TNBC.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Rad6 protein is overexpressed in aggressive breast cancers, particularly triple-negative breast cancer (TNBC).
- A small molecule inhibitor, SMI#9, targets Rad6 and shows cytotoxicity to cancer cells but has poor solubility.
- Nanoparticle drug delivery systems offer potential to improve solubility and targeting of therapeutic agents.
Purpose of the Study:
- To develop a nanotechnology-based drug delivery system for SMI#9 to improve its therapeutic efficacy in TNBC.
- To evaluate the activity and targeting specificity of SMI#9 conjugated to gold nanoparticles (SMI#9-GNP) in different TNBC subtypes.
- To assess the synergistic effect of SMI#9-GNP with cisplatin in TNBC treatment.
Main Methods:
- Chemical modification of SMI#9 for conjugation to gold nanoparticles (GNPs).
- In vitro evaluation of SMI#9 and SMI#9-GNP cytotoxicity in mesenchymal and basal TNBC cell lines.
- Assessment of SMI#9-GNP endocytosis and its combination therapy with cisplatin.
Main Results:
- SMI#9-GNP demonstrated targeted cytotoxicity in mesenchymal TNBC cells, while parent SMI#9 was effective in all TNBC cells.
- Endocytosis of SMI#9-GNP was compromised in basal TNBC cells due to aggregation.
- SMI#9-GNP synergistically enhanced cisplatin sensitivity in TNBC cells and spared normal breast cells.
- Released SMI#9 induced cell death via mitochondrial dysfunction and PARP-1 stabilization.
Conclusions:
- SMI#9-GNP represents a promising nanotechnology-based therapeutic strategy for Rad6-targeting in TNBC.
- The study highlights the potential of nanoparticle conjugation to overcome drug solubility limitations and improve cancer therapy.
- Combination therapy with SMI#9-GNP and cisplatin may offer a synergistic approach for treating chemo-resistant TNBC.
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