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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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Together we are improving prostate cancer diagnostic and treatment options

We have an update on our moustaches for Movember (It’s Movember time to grow a mo for a bro!) and we coordinated our plaid (for Dad) at the same time! Hopefully, your Movember was as successful. APCaRI wants to send a thank you to Movember and Prostate Cancer Canada for their Men’s Health Awareness Drives. How else can we get our moustaches AND plaid on at the same time!
In the spirit of gratitude, APCaRI also recognizes our research staff for their hard work and dedication to improving prostate cancer care and future outcomes AND the nurses, oncologists, and urologists who work every day to help the men and their families touched by prostate cancer. Please know that your devotion to the patients and their treatment needs is greatly appreciated.

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