af Hallstrom, Taija M.

Colis, Laureen

Enback, Juulia

Jaamaa, Sari

Jones, Richard J.

Laakkonen, Pirjo

Laiho, Marikki

Liu, Hester

Moore, Henna M.

Peltonen, Karita

Vaahtokari, Anne

PLoS ONE

PubMed

Helsingin yliopiston digitaalinen arkisto

Identification of Novel p53 Pathway Activating Small-Molecule Compounds Reveals Unexpected Similarities with Known Therapeutic Agents

Manipulation of the activity of the p53 tumor suppressor pathway has demonstrated potential benefit in preclinical mouse tumor models and has entered human clinical trials. We describe here an improved, extensive small-molecule chemical compound library screen for p53 pathway activation in a human cancer cell line devised to identify hits with potent antitumor activity. We uncover six novel small-molecule lead compounds, which activate p53 and repress the growth of human cancer cells. Two tested compounds suppress in vivo tumor growth in an orthotopic mouse model of human B-cell lymphoma. All compounds interact with DNA, and two activate p53 pathway in a DNA damage signaling-dependent manner. A further screen of a drug library of approved drugs for medicinal uses and analysis of gene-expression signatures of the novel compounds revealed similarities to known DNA intercalating and topoisomerase interfering agents and unexpected connectivities to known drugs without previously demonstrated anticancer activities. These included several neuroleptics, glycosides, antihistamines and adrenoreceptor antagonists. This unbiased screen pinpoints interference with the DNA topology as the predominant mean of pharmacological activation of the p53 pathway and identifies potential novel antitumor agents

Karita Peltonen

Laureen Colis

Hester Liu

Sari Jäämaa

Henna M Moore

Juulia Enbäck

Pirjo Laakkonen

Anne Vaahtokari

Richard J Jones

Taija M af Hällström

Marikki Laiho

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Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents.

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Transcription - guarding the genome by sensing DNA damage.

Wild-type p53: tumors can’t stand it.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2946317

Identification of Novel p53 Pathway Activating Small-Molecule Compounds Reveals Unexpected Similarities with Known Therapeutic Agents

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