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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Working to include Yukoners in APCaRI

APCaRI, represented by John Lewis and Catalina Vasquez, met with many Yukoners in Whitehorse recently to discuss the potential of including the North of 60 men in the registry and their samples in the biorepository. Sean Secord (photographed with John and Catalina), formerly with the Yukon Hospitals Foundation, talked with John on CBC Whitehorse radio about the challenges that Yukoners with cancer, and their families, have to manage and overcome to get testing and treatment. They are formidable; a recent article by Simkin et al., 2017 evaluated cancer mortality rates in the Yukon from 1999 to 2013 and found that they were elevated for prostate, female breast and lung, and colorectal cancers compared to both urban and rural populations in Canada South of the Yukon. The authors suggested that the high Yukon rates are, in part, due to the high percentage of Yukoners living in rural and very remote communities, making it necessary for patients to have to travel long distances for diagnoses and treatment. But even if the cancer patient lives in Whitehorse, (Yukon capital, population 25 085), cancer care options are limited due in part to a lack of oncologists and the specialized equipment needed.
John and Catalina met and had stimulating discussions with many people dedicated to improving cancer care in the North including the Yukon Ride for Dad organizers, representatives from the medical and laboratory communities and people living with cancer, and their families.
APCaRI is determined to find a way to include the Yukon men in the registry so that their valuable medical information and samples can be added to the prostate cancer research initiative and be an important part of improving prostate cancer diagnosis, treatment and care.

- Perrin Beatty