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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

Haynes, Brittany, Zhang, Yanhua, Liu, Fangchao, Li, Jing, Petit, Sarah, Kothayer, Hend, Bao, Xun, Westwell, Andrew David, Mao, Guangzhao and Shekhar, Malathy P.V. 2016. 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. Nanomedicine: Nanotechnology, Biology and Medicine 12 (3) , pp. 745-757. 10.1016/j.nano.2015.10.010

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Gold nanoparticles; Rad6; Poly(ADP-ribose) polymerase (PARP-1); lysosome; mitochondria; autophagy
Publisher: Elsevier
ISSN: 1549-9634
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 10 October 2015
Last Modified: 05 Jun 2017 00:58
URI: http://orca-mwe.cf.ac.uk/id/eprint/80784

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