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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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The Calgary Prostate Cancer Centre has the highest accrual for a novel ultrasound study in prostate cancer

“We have enrolled over 400 patients at our site, reaching our enrollment goal much faster than all other sites across North America. We are now planning on adding in 250 more patients to this trial because of the encouraging results found with the first arm of the trial. Our site tied with the highest accrual goal and surpassed all other sites to meet our enrollment goal.”

The study is a “Multi-Center trial of high-resolution transrectal ultrasound versus standard low-resolution transrectal ultrasound for the identification of clinically significant prostate cancer”

The only definitive method for diagnosing prostate cancer is through a prostate biopsy. This procedure includes the use of an ultrasound machine to guide both freezing needles and biopsy needles into the prostate. The ultrasound machine that is currently in use is a low-resolution ultrasound machine which means that although it is good at seeing the entire prostate gland to guide the needles, it is often unable to visualize the prostate in enough detail to be able to see different lesions and areas of concern within it. Thus, many biopsy samples are taken systematically with two samples from each section of the prostate. Recently a new ultrasound machine has been created that gives images of the prostate with much higher resolution, allowing the radiologist performing the biopsy to see details within the prostate that were previously inaccessible. A study using this new high-resolution ultrasound machine is being completed at the Prostate Cancer Centre to compare the adequacy of this new machine to detect prostate cancer over the standard low-resolution machine. Over 650 patients will be enrolled in this study!

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