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Autor(en) / Beteiligte
Titel
Abstract 5429: Cytotoxicity of AOH compounds targeting the interaction of caPCNA and its binding partners in human cancer cells
Ist Teil von
  • Cancer research (Chicago, Ill.), 2011-04, Vol.71 (8_Supplement), p.5429-5429
Ort / Verlag
American Association for Cancer Research (AACR)
Erscheinungsjahr
2011
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
  • Abstract Previously we reported the identification of an acidic isoform of proliferating cell nuclear antigen (caPCNA) in various cancer cells. Proliferating Cell Nuclear Antigen (PCNA) interacts with multiple binding partners to carry out vital cellular processes including DNA replication, DNA damage repair, and cell-cycle progression. We hypothesize that caPCNA performs similar functions specifically in cancer cells and, therefore, disrupting interactions of caPCNA with its binding partners will prevent necessary cellular functions, resulting in cytotoxicity to cancer cells. AOH compounds were generated based on a focused computer molecular “docking” search for small molecules that specifically targeted the interaction of caPCNA and its binding partner FEN1. MTT assays suggest that several AOH compounds have promising anti-proliferation effects in human breast and pancreatic cancer cells with EC50 values as low as or less than 10uM (lead compounds). To further evaluate the cytotoxicity of lead AOH compounds, clonogenic survival assays were performed in MCF-7 cells treated with the small molecules for 2 hours. Results showed that AOH compounds induced cytotoxicity in cancer cells in a dose-dependent manner. The IC50s of these compounds were between 10 to 20uM in MCF-7cells. To investigate the effects of the AOH compounds on DNA replication and the cell cycle, in vitro SV40 DNA replication assays and flow cytometric analysis were performed. The G2/M phase cell population was increased from 8% to 30-80% in MCF-7 cells treated with 25uM AOH compounds for 48 hours, indicating an induction of G2 arrest. AOH compound at 10uM inhibited in vitro DNA replication in malignant cell extracts by 70-80% relative to untreated correspondent cell extracts. Taken together, the potent cytotoxicity of AOH compounds in cancer cells is correlated with their inhibition of DNA replication and induction of cell cycle arrest. The compounds may be useful in the future for clinical cancer chemotherapy as a single anticancer agent and/or in combination with other anti-neoplastic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5429. doi:10.1158/1538-7445.AM2011-5429
Sprache
Englisch
Identifikatoren
ISSN: 0008-5472
eISSN: 1538-7445
DOI: 10.1158/1538-7445.AM2011-5429
Titel-ID: cdi_crossref_primary_10_1158_1538_7445_AM2011_5429

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