Effects of the novel DNA dependent protein kinase inhibitor, IC486241, on the DNA damage response to doxorubicin and cisplatin in breast cancer cells

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• 作者：David Davidson (1)
  Jeremy Grenier (1)
  Veronica Martinez-Marignac (1)
  Lilian Amrein (1)
  May Shawi (1)
  Marc Tokars (2)
  Raquel Aloyz (1)
  Lawrence Panasci (1) lpanasci@hotmail.com
• 刊名：Investigational New Drugs
• 出版年：2012
• 出版时间：August 2012
• 年：2012
• 卷：30
• 期：4
• 页码：1736-1742
• 全文大小：437.1 KB
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• 作者单位：1. Montreal Centre for Experimental Therapeutics in Cancer鈥擲egal Cancer Center鈥擫ady Davis Institute鈥擩ewish General Hospital, McGill University, 3755, C么te Sainte Catherine Road, Montr茅al, Qu茅bec H3T 1E2, Canada2. Preclinical Development, Luitpold Pharmaceuticals, Inc, 800 Adams Avenue, Suite 100, Norristown, PA 19403, USA
• ISSN：1573-0646

文摘

The purpose of this study was to determine the degree to which the novel DNA-PKcs inhibitor, IC486241 (ICC), synergizes the cytotoxicity of DNA damaging agents in 3 genetically diverse breast cancer cell lines. The sulforhodamine B (SRB) assay was employed as a primary screening method to determine the in-vitro cytotoxicity and the degree of synergy of ICC in combination with the topoisomerase II inhibitor, doxorubicin, or the DNA cross linking agent, cisplatin. Molecular mechanisms underlying drug toxicity were probed using immunostaining and flow cytometry, as well as, the alkaline comet assay to detect DNA damage. In this study, improved cytotoxicity and significant synergy were observed with both anticancer agents in the presence of nontoxic concentrations of ICC. Moreover, ICC decreased doxorubicin-induced DNA-PKcs autophosphorylation on Ser2056 and increased doxorubicin-induced DNA fragmentation. In conclusion, the novel DNA-PKcs inhibitor, ICC, synergistically sensitized 3 breast cancer cell lines to doxorubicin and cisplatin. Enhanced efficacy of doxorubicin was achieved by inhibiting non-homologous end joining resulting in increased accumulation of DNA damage.