An image-based, high-throughput screening assay for molecules that induce excess DNA replication in human cancer cells

Previous studies have shown DNA re-replication can be induced in cells derived from human cancers under conditions in which it is not possible for cells derived from normal tissues. Because DNA re-replication induces cell death, this strategy could be applied to the discovery of potential anticancer...

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Bibliographic Details
Published in:Molecular cancer research 2011-03, Vol.9 (3), p.294-310
Main Authors: Zhu, Wenge, Lee, Chrissie Y, Johnson, Ronald L, Wichterman, Jennifer, Huang, Ruili, DePamphilis, Melvin L
Format: Article
Language:English
Subjects:
Antineoplastic Agents - classification
Antineoplastic Agents - pharmacology
Cell Death - drug effects
Cell Line, Tumor - drug effects
Cell Line, Tumor - pathology
Cell Proliferation - drug effects
Disulfiram - pharmacology
DNA Replication - drug effects
Drug Screening Assays, Antitumor
High-Throughput Screening Assays - methods
Humans
Indoles - pharmacology
Neoplasms - drug therapy
Neoplasms - genetics
Neoplasms - pathology
Pargyline - analogs & derivatives
Pargyline - pharmacology
Small Molecule Libraries - analysis
Sulfonamides - pharmacology
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Summary:Previous studies have shown DNA re-replication can be induced in cells derived from human cancers under conditions in which it is not possible for cells derived from normal tissues. Because DNA re-replication induces cell death, this strategy could be applied to the discovery of potential anticancer therapeutics. Therefore, an imaging assay amenable to high-throughput screening was developed that measures DNA replication in excess of four genomic equivalents in the nuclei of intact cells and indexes cell proliferation. This assay was validated by screening a library of 1,280 bioactive molecules on both normal and tumor-derived cells where it proved more sensitive than current methods for detecting excess DNA replication. This screen identified known inducers of excess DNA replication, such as inhibitors of microtubule dynamics, and novel compounds that induced excess DNA replication in both normal and cancer cells. In addition, two compounds were identified that induced excess DNA replication selectively in cancer cells and one that induced endocycles selectively in cancer cells. Thus, this assay provides a new approach to the discovery of compounds useful for investigating the regulation of genome duplication and for the treatment of cancer.
ISSN:1541-7786
1557-3125
DOI:10.1158/1541-7786.MCR-10-0570