Abstract
Inhibitors of poly(ADP-ribose) polymerase (PARP) are promising anticancer drugs, particularly for the treatment of tumors deficient in the DNA damage response (DDR). However, it is challenging to design effective therapeutic strategies for use of these compounds against cancers without DDR deficiencies. In this context, combination therapies in which PARP inhibitors are used alongside DDR inhibitors have elicited a great deal of interest. Curcumin, a component of turmeric (Curcuma longa), has been tested in clinical studies for its chemosensitizing potential; however, the mechanisms of chemosensitization by curcumin have not been fully elucidated. This study demonstrates that curcumin suppresses three major DDR pathways: non-homologous end joining (NHEJ), homologous recombination (HR) and the DNA damage checkpoint. Curcumin suppresses the histone acetylation at DNA double-strand break (DSB) sites by inhibiting histone acetyltransferase activity, thereby reducing recruitment of the key NHEJ factor KU70/KU80 to DSB sites. Curcumin also suppresses HR by reducing expression of the BRCA1 gene, which regulates HR, by impairing histone acetylation at the BRCA1 promoter. Curcumin also inhibits ataxia telangiectasia and Rad3-related protein (ATR) kinase (IC50 in vitro = 493 nM), resulting in impaired activation of ATR-CHK1 signaling, which is necessary for HR and the DNA damage checkpoint pathway. Thus, curcumin suppresses three DDR pathways by inhibiting histone acetyltransferases and ATR. Concordantly, curcumin sensitizes cancer cells to PARP inhibitors by enhancing apoptosis and mitotic catastrophe via inhibition of both the DNA damage checkpoint and DSB repair. Our results indicate that curcumin is a promising sensitizer for PARP inhibitor-based therapy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylation / drug effects
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Ataxia Telangiectasia Mutated Proteins / metabolism
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BRCA1 Protein / antagonists & inhibitors
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BRCA1 Protein / metabolism
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Blotting, Western
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Cell Cycle Checkpoints
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Cell Proliferation / drug effects
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Checkpoint Kinase 1
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Cobalt Radioisotopes
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Curcumin / pharmacology*
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DNA Damage / drug effects*
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DNA Damage / radiation effects
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DNA Repair / drug effects
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DNA Repair / radiation effects
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Enzyme Inhibitors / pharmacology
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Gamma Rays
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Histone Acetyltransferases / metabolism
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Histones / metabolism
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Homologous Recombination / drug effects*
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Homologous Recombination / radiation effects
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Humans
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Mice
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / pathology*
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / metabolism
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerase Inhibitors*
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Promoter Regions, Genetic
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Protein Kinases / metabolism
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Sialoglycoproteins / antagonists & inhibitors
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Sialoglycoproteins / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / radiation effects
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Tumor Cells, Cultured
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p300-CBP Transcription Factors / antagonists & inhibitors
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p300-CBP Transcription Factors / metabolism
Substances
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Antineoplastic Agents
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BRCA1 Protein
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BRCA1 protein, human
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Cobalt Radioisotopes
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Enzyme Inhibitors
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Histones
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Peptide Fragments
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Poly(ADP-ribose) Polymerase Inhibitors
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Sialoglycoproteins
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bone sialoprotein (35-62), human
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Protein Kinases
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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CHEK1 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Curcumin