Identification of small molecules that selectively induce excess DNA replication in cancer cells

DNA replication is highly regulated by multiple pathways to ensure that DNA replication initiates once and only once per cell cycle. Loss of this control may result in excess DNA replication. Previous studies have shown that depleting Geminin, a DNA replication inhibitor, can selectively induce excess DNA replication in cancer cells but not in normal cells, suggesting that anti-Geminin is a potential approach for cancer therapy. To identify Geminin inhibitors, we conducted a High Throughput Screening (HTS) assay to identify small molecules that can selectively induce excess DNA replication in cancer cells. Using this HTS approach against NIH Molecular Libraries Small Molecule Repository, we identified 6 compounds that selectively induced excess DNA replication. The follow-up study suggests that X9C is one potent compound that induces excess DNA replication. Our study indicates that X9C can selectively induce excess DNA replication and subsequent cell death in cancer cells. X9C also causes G2/M phase block and multi-spindle defect which triggers apoptosis pathway in a p53-dependent manner. Overall, these observations suggest that X9C might target spindle- kinetochore alignment. The selectivity and cellular properties of X9C make it a potential candidate for future clinical application.

Author

• Yang, Yi

Language

• en

Keyword

• small molecules
• excess DNA replication
• Drug discovery
• Mitotic block
• High-throughput screening

Date created

• 2012

Type of Work

• Master's Thesis

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Biochemistry and Molecular Biology

Degree

• M.S.

Advisor

• Zhu, Wenge

Committee Member(s)

• Li, Da-Qiang

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/cf95jb630