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Action of a Novel Anticancer Agent, CHS 828, on Mouse Fibroblasts

Increased Sensitivity of Cells Lacking Poly (ADP-Ribose) Polymerase-1¹

Henrik Lövborg, Jacek Wojciechowski, Rolf Larsson and Józefa Wsierska-Gdek²

Department of Clinical Pharmacology, Uppsala University Hospital, Uppsala, Sweden [H. L., R. L.,] and the Institute of Cancer Research, University of Vienna, Vienna, Austria [J. W., J. W-G.]

We observed stronger cytotoxic effect of CHS 828 on poly(ADP-ribose) polymerase-1(PARP-1) knock-out cells as compared with the normal counterpart. The proliferation of PARP-1 -/- cells was inhibited by a drug concentration 3-fold lower than that in the normal cells. The monitoring of p53 levels revealed that CHS 828 induced p53 response in a dose-dependent manner in only normal cells. The drug, however, failed to activate the p53 protein in PARP-1-deficient cells even after combined treatment with multidrug-resistant modulators. These results show that the PARP-1 inactivation sensitizes cells to the novel anticancer drug CHS 828 and that the drug is able to activate different cellular pathways depending on PARP-1 status.

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