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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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Member of the APCaRI Training Program will present a poster at CARO ASM 2017 – Toronto

Congratulations to Dr. Deepak Dinakaran for getting his abstract “Comparison of Post-Radiotherapy Prostate Specific Antigen drop kinetics between External Beam Radiotherapy and Brachytherapy” accepted as a poster presentation at the Canadian Association of Radiation Oncology Annual Scientific Meeting (CARO ASM) 2017.

The 2017 CARO Annual Scientific Meeting will be held at the Hilton Toronto in Toronto, ON September 13-16, 2017.  This conference is for Radiation Oncologists, Medical Physicists, Radiation Therapists, Basic Science Researchers, Oncology Nurses, Administrators, as well as their trainees. All healthcare professionals involved in the care of oncology patients are also welcome to attend.

Dr. Dinakaran extracted and analyzed clinical data from the Alberta Prostate Cancer Registry for this study.

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