Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models

Jeffrey M. Albert, Carolyn Cao, Woon Kim Kwang, Christopher D. Willey, Ling Geng, Dakai Xiao, Hong Wang, Alan Sandler, David H. Johnson, Alexander D. Colevas, Jennifer Low, Mace L. Rothenberg, Bo Lu

Research output: Contribution to journalArticle

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Abstract

Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation. Experimental Design: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature. Results: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone γ-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase - mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis. Conclusions: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.

Original languageEnglish (US)
Pages (from-to)3033-3042
Number of pages10
JournalClinical Cancer Research
Volume13
Issue number10
DOIs
StatePublished - May 15 2007

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Poly(ADP-ribose) Polymerases
Lung Neoplasms
Cell Death
Growth
Neoplasms
Radiation
Staining and Labeling
DNA Breaks
DNA Repair
Deoxyribonucleotides
Adenosine Diphosphate Ribose
Inhibition (Psychology)
Radiation Tolerance
Autophagy
von Willebrand Factor
Transferases
Ionizing Radiation
Tumor Burden
Histones
veliparib

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. / Albert, Jeffrey M.; Cao, Carolyn; Kwang, Woon Kim; Willey, Christopher D.; Geng, Ling; Xiao, Dakai; Wang, Hong; Sandler, Alan; Johnson, David H.; Colevas, Alexander D.; Low, Jennifer; Rothenberg, Mace L.; Lu, Bo.

In: Clinical Cancer Research, Vol. 13, No. 10, 15.05.2007, p. 3033-3042.

Research output: Contribution to journalArticle

Albert, JM, Cao, C, Kwang, WK, Willey, CD, Geng, L, Xiao, D, Wang, H, Sandler, A, Johnson, DH, Colevas, AD, Low, J, Rothenberg, ML & Lu, B 2007, 'Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models', Clinical Cancer Research, vol. 13, no. 10, pp. 3033-3042. https://doi.org/10.1158/1078-0432.CCR-06-2872
Albert, Jeffrey M. ; Cao, Carolyn ; Kwang, Woon Kim ; Willey, Christopher D. ; Geng, Ling ; Xiao, Dakai ; Wang, Hong ; Sandler, Alan ; Johnson, David H. ; Colevas, Alexander D. ; Low, Jennifer ; Rothenberg, Mace L. ; Lu, Bo. / Inhibition of poly(ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models. In: Clinical Cancer Research. 2007 ; Vol. 13, No. 10. pp. 3033-3042.
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AU - Albert, Jeffrey M.

AU - Cao, Carolyn

AU - Kwang, Woon Kim

AU - Willey, Christopher D.

AU - Geng, Ling

AU - Xiao, Dakai

AU - Wang, Hong

AU - Sandler, Alan

AU - Johnson, David H.

AU - Colevas, Alexander D.

AU - Low, Jennifer

AU - Rothenberg, Mace L.

AU - Lu, Bo

PY - 2007/5/15

Y1 - 2007/5/15

N2 - Purpose: Poly(ADP-ribose) polymerase-1 (PARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation. Experimental Design: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature. Results: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone γ-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated doses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase - mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis. Conclusions: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer.

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