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Effects of Parp Inhibition on Drug and FAS-Induced Apoptosis in Leukaemic Cells

  • Chapter
Drug Resistance in Leukemia and Lymphoma III

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 457))

Abstract

Poly (ADP-ribose) polymerase (PARP) is activated following binding to DNA strand breaks and is cleaved in cells undergoing apoptosis. Work predominantly in murine systems has suggested that inhibitors of PARP might potentiate the effects of chemotherapeutic agents and be used as adjuncts to cancer therapy. Therefore, we studied the role of PARP in drug-induced apoptosis in HL-60, myeloid leukaemia cells and found that pre-treatment with 3-aminobenzamide (3 AB) or 6(5H)- phenanthridinone, inhibitors of PARP, resulted in resistance to, rather than potentiation of apoptotic death induced by DNA-damaging agents, idarubicin, etoposide and fludarabine, as determined by flow cytometry, following propidium iodide staining. 3AB treated CEM/VLB100, mdr-expressing human lymphoblastic leukaemia cells were also found to be more resistant to idarubicin compared to cells treated with idarubicin alone, however, apoptosis was not reduced in parental CCRF-CEM cells under the same conditions. Similar results were obtained using agents with primary modes of action which do not involve DNA damage, vinblastine and a fas-ligating antibody (CH11). The precise role of PARP has yet to be defined but might involve effects on cell cycle progression.

We conclude that PARP activation appears to be involved in apoptosis in certain leukaemic cell lines and that these effects are independent of lineage or p-glycoprotein. Constitutive failure to activate PARP might be responsible for conferring resistance to apoptosis.

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Authors and Affiliations

  1. Department of Haematology, St. Bartholomew’s and Royal London School of Medicine, UK

    Dr. Deborah S. Richardson, Paul D. Allen, Stephen M. Kelsey & Adrian C. Newland

  2. Department of Haematology, Royal London Hospital, Whitechapel Road, London, E1 1BB, UK

    Dr. Deborah S. Richardson

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  1. University Hospital Vrije Universiteit, Amsterdam, The Netherlands

    G. J. L. Kaspers , R. Pieters  & A. J. P. Veerman ,  & 

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Richardson, D.S., Allen, P.D., Kelsey, S.M., Newland, A.C. (1999). Effects of Parp Inhibition on Drug and FAS-Induced Apoptosis in Leukaemic Cells. In: Kaspers, G.J.L., Pieters, R., Veerman, A.J.P. (eds) Drug Resistance in Leukemia and Lymphoma III. Advances in Experimental Medicine and Biology, vol 457. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4811-9_29

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  • DOI: https://doi.org/10.1007/978-1-4615-4811-9_29

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