title: Gold nanoparticle conjugated Rad6 inhibitor induces cell death in triple negative breast cancer cells by inducing mitochondrial dysfunction and PARP-1 hyperactivation: Synthesis and characterization.
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.
  
  
  BACKGROUND
  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.
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Haynes
authors.affiliation: Department of Chemical Engineering and Materials Science, Wayne State University College of Engineering, Detroit, MI, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Chemical Engineering and Materials Science, Wayne State University College of Engineering, Detroit, MI, USA.
authors.forename: Fangchao
authors.initials: F
authors.lastname: Liu
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Petit
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK; Faculty of Pharmacy, Zagazig University, Egypt.
authors.forename: Hend
authors.initials: H
authors.lastname: Kothayer
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA.
authors.forename: Xun
authors.initials: X
authors.lastname: Bao
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Westwell
authors.affiliation: Department of Chemical Engineering and Materials Science, Wayne State University College of Engineering, Detroit, MI, USA. Electronic address: gzmao@eng.wayne.edu.
authors.forename: Guangzhao
authors.initials: G
authors.lastname: Mao
authors.affiliation: Karmanos Cancer Institute, Detroit, MI, USA; Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Pathology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: shekharm@karmanos.org.
authors.forename: Malathy P V
authors.initials: MPV
authors.lastname: Shekhar
mesh_terms: D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006046:Gold / Q000737:chemistry*; D006801:Humans; D053768:Metal Nanoparticles / Q000737:chemistry*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006046:Gold; C471545:UBE2A protein, human; D044763:Ubiquitin-Conjugating Enzymes; D000071137:Poly (ADP-Ribose) Polymerase-1
keywords: Autophagy; Gold nanoparticles; Lysosome; Mitochondria; Poly(ADP-ribose) polymerase (PARP-1); Rad6