Haynes, Brittany, Zhang, Yanhua, Liu, Fangchao, Li, Jing, Petit, Sarah, Kothayer, Hend, Bao, Xun, Westwell, Andrew D.  ORCID: https://orcid.org/0000-0002-5166-9236, 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: | 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 |
| Additional Information: | Released with a Creative Commons Attribution Non-Commercial No Derivatives License (CC BY-NC-ND) |
| Publisher: | Elsevier |
| ISSN: | 1549-9634 |
| Date of First Compliant Deposit: | 30 March 2016 |
| Date of Acceptance: | 10 October 2015 |
| Last Modified: | 21 Nov 2024 17:30 |
| URI: | https://orca.cardiff.ac.uk/id/eprint/80784 |
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