PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme involved in processes of cell cycle regulation, DNA repair, transcription, and replication. Hyperactivity of PARP-1 induced by changes in cell homeostasis promotes development of chronic pathological processes leading to cell death during various metabolic disorders, cardiovascular and neurodegenerative diseases. In contrast, tumor growth is accompanied by a moderate activation of PARP-1 that supports survival of tumor cells due to enhancement of DNA lesion repair and resistance to therapy by DNA damaging agents. That is why PARP inhibitors (PARPi) are promising agents for the therapy of tumor and metabolic diseases. A PARPi family is rapidly growing partly due to natural polyphenols discovered among plant secondary metabolites. This review describes mechanisms of PARP-1 participation in the development of various pathologies, analyzes multiple PARP-dependent pathways of cell degeneration and death, and discusses representative plant polyphenols, which can inhibit PARP-1 directly or suppress unwanted PARP-dependent cellular processes.

Keywords: PARP-1; PARP-1 inhibitors; polyphenols.

Figure 1

PARP-1 hyperactivation as an aggravating factor in the development of various diseases. Gray dotted lines indicate “vicious circles” when PARP-1 hyperactivation initiated by inflammation, cardiovascular, neurodegenerative or diabetic pathology leads to an increase in the severity of the disease.

Figure 2

PARP-1 dependent cell death. UV—ultraviolet light, ROS—reactive oxygen species overproduced in oxidative stress, RNS—reactive nitrogen species (e.g., nitric oxide NO) overproduced in nitrosative stress. See text for detail.

Figure 3

PARP-1-dependent transcriptional activation of genes encoding pro-inflammatory cytokines in eukaryotic cells. See text for details. Abbreviations: JAK—Janus kinase; PIP3—phosphatidylinositol (3,4,5)-trisphosphate; MAPKKKs—Mitogen-Activated Protein (MAP) kinase kinase kinases; MAPKKs—Mitogen-activated protein kinase kinases; MAPKs—mitogen-activated protein kinases; STAT—members of the signal transducer and activator of transcription protein family; AKT—subfamily of serine/threonine kinases; p38—p38 mitogen-activated protein kinases; JNK—c-Jun N-terminal kinases; ERKs—extracellular signal-regulated kinases; IL-l, IL6, IL-8—interleukins 1, 6, 8, p300/CRB—p300/CREB-binding protein complex, TNFα—tumor necrosis factor α.

Figure 4

A role of PARP-1 in the tumor progression and development of its drug resistance. HSP70—heat shock protein 70.

Figure 5

Synthetic PARPi approved for use in oncology. IC50 values (PARPi concentrations inducing 50% inhibition of PARP-1 activity) are cited from [19].

Figure 6

Plant polyphenols with known pharmacological properties.

Figure 7

Classes of polyphenols, whose representatives were found to act as PARPi, and the observed polyphenol-induced regulatory effects. ↑ - up-regulated, ↓- down-regulated.