Journal
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
Volume 12, Issue 3, Pages 745-757Publisher
ELSEVIER
DOI: 10.1016/j.nano.2015.10.010
Keywords
Gold nanoparticles; Rad6; Poly(ADP-ribose) polymerase (PARP-1); Lysosome; Mitochondria; Autophagy
Funding
- National Cancer Institute [R21CA178117]
- Molecular Therapeutics Program Grant from Karmanos Cancer Institute
- National Science Foundation [CHE1404285]
- National Institutes of Health [R01HD031550]
- Initiative for Maximizing Student Diversity (IMSD) [GM058905]
- National Research Service Award from NIH [T32-CA009531]
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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.
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