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Cancer Res. 2014 Jul 1;74(13):3546-55. doi: 10.1158/0008-5472.CAN-13-3220. Epub 2014 Apr 21.

The RAD51-stimulatory compound RS-1 can exploit the RAD51 overexpression that exists in cancer cells and tumors.

Author information

1
Authors' Affiliations: Department of Radiation and Cellular Oncology.
2
Department of Medicinal Chemistry and Pharmacognosy, Drug Discovery Program, University of Illinois at Chicago, Chicago, Illinois.
3
Authors' Affiliations: Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research.
4
Authors' Affiliations: Department of Radiation and Cellular Oncology, Department of Molecular Genetics and Cell Biology, University of Chicago; and.
5
Authors' Affiliations: Department of Radiation and Cellular Oncology, pconnell@radonc.uchicago.edu.

Abstract

RAD51 is the central protein that catalyzes DNA repair via homologous recombination, a process that ensures genomic stability. RAD51 protein is commonly expressed at high levels in cancer cells relative to their noncancerous precursors. High levels of RAD51 expression can lead to the formation of genotoxic RAD51 protein complexes on undamaged chromatin. We developed a therapeutic approach that exploits this potentially toxic feature of malignancy, using compounds that stimulate the DNA-binding activity of RAD51 to promote cancer cell death. A panel of immortalized cell lines was challenged with the RAD51-stimulatory compound RS-1. Resistance to RS-1 tended to occur in cells with higher levels of RAD54L and RAD54B, which are Swi2/Snf2-related translocases known to dissociate RAD51 filaments from dsDNA. In PC3 prostate cancer cells, RS-1-induced lethality was accompanied by the formation of microscopically visible RAD51 nuclear protein foci occurring in the absence of any DNA-damaging treatment. Treatment with RS-1 promoted significant antitumor responses in a mouse model, providing proof-of-principle for this novel therapeutic strategy.

PMID:
24753542
PMCID:
PMC4079730
DOI:
10.1158/0008-5472.CAN-13-3220
[Indexed for MEDLINE]
Free PMC Article

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