Publications

Publications

Small Molecule Inhibitors of ERCC1-XPF Protein-Protein Interaction Synergize Alkylating Agents in Cancer Cells

By:
Contributors: Jack Tuszynski Research Group
Mol Pharmacol. 2013 Jul;84(1):12-24. doi: 10.1124/mol.112.082347. Epub 2013 Apr 11.

Abstract

The benefit of cancer chemotherapy based on alkylating agents is limited because of the action of DNA repair enzymes, which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures with use of the National Cancer Institute diversity set and a panel of DrugBank small molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC 130813 [4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2-[(4-methyl-1-piperazinyl)methyl]] was shown to act synergistically with cisplatin and mitomycin C; to increase UVC-mediated cytotoxicity; to modify DNA repair as indicated by the staining of phosphorylated H2AX; and to disrupt interaction between ERCC1 and XPF in cells. In addition, using the Biacore technique, we showed that this compound interacts with the domain of XPF responsible for interaction with ERCC1. This study shows that small molecules targeting the protein-protein interaction of ERCC1 and XPF can be developed to enhance the effects of alkylating agents on cancer cells.

 

PubMed

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New platform for prostate cancer diagnosis to be presented at ISEV 2017

The Lewis Research Group will present exciting results about new blood tests for prostate cancer during 3 talks at the upcoming 2017 International Society of Extracellular Vesicles (ISEV) annual meeting in Toronto (May 18-21). ISEV is a global society of researchers studying exosomes and microvesicles, which are the exciting new focus of cancer therapy and diagnosis.

Dr. Desmond Pink will speak about “Microflow cytometry: The Apogee A50 is a sensitive standard tool for extracellular vesicle analyses in liquid biopsies”, Robert Paproski’s presentation is entitled “Using machine learning of extracellular vesicle flow cytometry to build predictive fingerprints for prostate cancer diagnosis”, and Dr. John Lewis will speak about “An extracellular vesicle blood fingerprint distinguishes between patients with indolent and aggressive prostate cancer at diagnosis”.

The team is looking forward to sharing these key advances that were made possible through the APCaRI prospective cohort.

- John Lewis