International Journal of Molecular Sciences

Editorial

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3 pages, 186 KiB

Open AccessEditorial

Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach

by Konstantin P. Volcho and Olga I. Lavrik

Int. J. Mol. Sci. 2023, 24(9), 7954; https://doi.org/10.3390/ijms24097954 - 27 Apr 2023

Cited by 1 | Viewed by 1150

Abstract

The DNA repair system plays a crucial role in maintaining the integrity of the genome [...] Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

Research

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18 pages, 3923 KiB

Open AccessArticle

New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1

by Nadezhda S. Dyrkheeva, Aleksandr S. Filimonov, Olga A. Luzina, Kristina A. Orlova, Irina A. Chernyshova, Tatyana E. Kornienko, Anastasia A. Malakhova, Sergey P. Medvedev, Alexandra L. Zakharenko, Ekaterina S. Ilina, Rashid O. Anarbaev, Konstantin N. Naumenko, Kristina V. Klabenkova, Ekaterina A. Burakova, Dmitry A. Stetsenko, Suren M. Zakian, Nariman F. Salakhutdinov and Olga I. Lavrik

Int. J. Mol. Sci. 2021, 22(21), 11336; https://doi.org/10.3390/ijms222111336 - 20 Oct 2021

Cited by 15 | Viewed by 2550

Abstract

Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the [...] Read more.

Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC₅₀ values in the 1.4–25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the compounds. A five-membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an uncompetitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound 10a showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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17 pages, 3374 KiB

Open AccessArticle

Inhibitors of Nucleotide Excision Repair Decrease UVB-Induced Mutagenesis—An In Vitro Study

by Eszter Fidrus, Csaba Hegedűs, Eszter Anna Janka, György Paragh, Gabriella Emri and Éva Remenyik

Int. J. Mol. Sci. 2021, 22(4), 1638; https://doi.org/10.3390/ijms22041638 - 6 Feb 2021

Cited by 4 | Viewed by 3441

Abstract

The high incidence of skin cancers in the Caucasian population is primarily due to the accumulation of DNA damage in epidermal cells induced by chronic ultraviolet B (UVB) exposure. UVB-induced DNA photolesions, including cyclobutane–pyrimidine dimers (CPDs), promote mutations in skin cancer driver genes. [...] Read more.

The high incidence of skin cancers in the Caucasian population is primarily due to the accumulation of DNA damage in epidermal cells induced by chronic ultraviolet B (UVB) exposure. UVB-induced DNA photolesions, including cyclobutane–pyrimidine dimers (CPDs), promote mutations in skin cancer driver genes. In humans, CPDs are repaired by nucleotide excision repair (NER). Several commonly used and investigational medications negatively influence NER in experimental systems. Despite these molecules’ ability to decrease NER activity in vitro, the role of these drugs in enhancing skin cancer risk is unclear. In this study, we investigated four molecules (veliparib, resveratrol, spironolactone, and arsenic trioxide) with well-known NER-inhibitory potential in vitro, using UVB-irradiated CHO epithelial and HaCaT immortalized keratinocyte cell lines. Relative CPD levels, hypoxanthine phosphoribosyltransferase gene mutation frequency, cell viability, cell cycle progression, and protein expression were assessed. All four molecules significantly elevated CPD levels in the genome 24 h after UVB irradiation. However, veliparib, spironolactone, and arsenic trioxide reduced the mutagenic potential of UVB, while resveratrol did not alter UVB-induced mutation formation. UVB-induced apoptosis was enhanced by spironolactone and arsenic-trioxide treatment, while veliparib caused significantly prolonged cell cycle arrest and increased autophagy. Spironolactone also enhanced the phosphorylation level of mammalian target of rapamycin (mTOR), while arsenic trioxide modified UVB-driven mitochondrial fission. Resveratrol induced only mild changes in the cellular UVB response. Our results show that chemically inhibited NER does not result in increased mutagenic effects. Furthermore, the UVB-induced mutagenic potential can be paradoxically mitigated by NER-inhibitor molecules. We identified molecular changes in the cellular UVB response after NER-inhibitor treatment, which may compensate for the mitigated DNA repair. Our findings show that metabolic cellular response pathways are essential to consider in evaluating the skin cancer risk–modifying effects of pharmacological compounds. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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21 pages, 3338 KiB

Open AccessArticle

Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair

by Sergei Boichuk, Firuza Bikinieva, Ilmira Nurgatina, Pavel Dunaev, Elena Valeeva, Aida Aukhadieva, Alexey Sabirov and Aigul Galembikova

Int. J. Mol. Sci. 2020, 21(22), 8842; https://doi.org/10.3390/ijms21228842 - 22 Nov 2020

Cited by 14 | Viewed by 3105

Abstract

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair [...] Read more.

Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic effects of topoisomerase II inhibitor, doxorubicin (Dox) in soft tissue sarcomas (STS) and gastrointestinal stromal tumors (GIST) in vitro. Blocking of AKT signaling (MK-2206) enhanced cytotoxic and pro-apoptotic effects of Dox in vast majority of STS and GIST cell lines. The phosphorylated form of Akt co-immunoprecipitates with Rad51 after Dox-induced DNA damage, whereas Akt inhibition interrupts this interaction and decreases Rad51 protein level by enhancing protein instability via proteasome-dependent degradation. Inhibition of Akt signaling in Dox-treated cells was associated with the increased number of γ-H2AX-positive cells, decrease of Rad51 foci formation and its colocalization with γ-H2AX foci, thereby revealing unsuccessful DDR events. This was also in consistency with an increase of tail moment (TM) and olive tail moment (OTM) in Dox-treated GIST and STS cells cultured in presence of Akt inhibitor after Dox washout. Altogether, our data illustrates that inhibition of AKT signaling is STS and GIST might potentiate the cytotoxic effect of topoisomerase II inhibitors via attenuating the homology-mediated DNA repair. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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22 pages, 4452 KiB

Open AccessArticle

PARP Inhibitor Olaparib Causes No Potentiation of the Bleomycin Effect in VERO Cells, Even in the Presence of Pooled ATM, DNA-PK, and LigIV Inhibitors

by Valentina Perini, Michelle Schacke, Pablo Liddle, Salomé Vilchez-Larrea, Deborah J. Keszenman and Laura Lafon-Hughes

Int. J. Mol. Sci. 2020, 21(21), 8288; https://doi.org/10.3390/ijms21218288 - 5 Nov 2020

Cited by 3 | Viewed by 3032

Abstract

Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) [...] Read more.

Poly(ADP-ribosyl)polymerase (PARP) synthesizes poly(ADP-ribose) (PAR), which is anchored to proteins. PAR facilitates multiprotein complexes’ assembly. Nuclear PAR affects chromatin’s structure and functions, including transcriptional regulation. In response to stress, particularly genotoxic stress, PARP activation facilitates DNA damage repair. The PARP inhibitor Olaparib (OLA) displays synthetic lethality with mutated homologous recombination proteins (BRCA-1/2), base excision repair proteins (XRCC1, Polβ), and canonical nonhomologous end joining (LigIV). However, the limits of synthetic lethality are not clear. On one hand, it is unknown whether any limiting factor of homologous recombination can be a synthetic PARP lethality partner. On the other hand, some BRCA-mutated patients are not responsive to OLA for still unknown reasons. In an effort to help delineate the boundaries of synthetic lethality, we have induced DNA damage in VERO cells with the radiomimetic chemotherapeutic agent bleomycin (BLEO). A VERO subpopulation was resistant to BLEO, BLEO + OLA, and BLEO + OLA + ATM inhibitor KU55933 + DNA-PK inhibitor KU-0060648 + LigIV inhibitor SCR7 pyrazine. Regarding the mechanism(s) behind the resistance and lack of synthetic lethality, some hypotheses have been discarded and alternative hypotheses are suggested. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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16 pages, 4143 KiB

Open AccessArticle

The First Berberine-Based Inhibitors of Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), an Important DNA Repair Enzyme

by Elizaveta D. Gladkova, Ivan V. Nechepurenko, Roman A. Bredikhin, Arina A. Chepanova, Alexandra L. Zakharenko, Olga A. Luzina, Ekaterina S. Ilina, Nadezhda S. Dyrkheeva, Evgeniya M. Mamontova, Rashid O. Anarbaev, Jóhannes Reynisson, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik

Int. J. Mol. Sci. 2020, 21(19), 7162; https://doi.org/10.3390/ijms21197162 - 28 Sep 2020

Cited by 13 | Viewed by 3036

Abstract

A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity [...] Read more.

A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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18 pages, 3453 KiB

Open AccessArticle

Functional Role of N-Terminal Extension of Human AP Endonuclease 1 In Coordination of Base Excision DNA Repair via Protein–Protein Interactions

by Nina Moor, Inna Vasil’eva and Olga Lavrik

Int. J. Mol. Sci. 2020, 21(9), 3122; https://doi.org/10.3390/ijms21093122 - 28 Apr 2020

Cited by 9 | Viewed by 3363

Abstract

Human apurinic/apyrimidinic endonuclease 1 (APE1) has multiple functions in base excision DNA repair (BER) and other cellular processes. Its eukaryote-specific N-terminal extension plays diverse regulatory roles in interaction with different partners. Here, we explored its involvement in interaction with canonical BER proteins. Using [...] Read more.

Human apurinic/apyrimidinic endonuclease 1 (APE1) has multiple functions in base excision DNA repair (BER) and other cellular processes. Its eukaryote-specific N-terminal extension plays diverse regulatory roles in interaction with different partners. Here, we explored its involvement in interaction with canonical BER proteins. Using fluorescence based-techniques, we compared binding affinities of the full-length and N-terminally truncated forms of APE1 (APE1NΔ35 and APE1NΔ61) for functionally and structurally different DNA polymerase β (Polβ), X-ray repair cross-complementing protein 1 (XRCC1), and poly(adenosine diphosphate (ADP)-ribose) polymerase 1 (PARP1), in the absence and presence of model DNA intermediates. Influence of the N-terminal truncation on binding the AP site-containing DNA was additionally explored. These data suggest that the interaction domain for proteins is basically formed by the conserved catalytic core of APE1. The N-terminal extension being capable of dynamically interacting with the protein and DNA partners is mostly responsible for DNA-dependent modulation of protein–protein interactions. Polβ, XRCC1, and PARP1 were shown to more efficiently regulate the endonuclease activity of the full-length protein than that of APE1NΔ61, further suggesting contribution of the N-terminal extension to BER coordination. Our results advance the understanding of functional roles of eukaryote-specific protein extensions in highly coordinated BER processes. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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11 pages, 1210 KiB

Open AccessArticle

Molecular Mechanisms of PARP-1 Inhibitor 7-Methylguanine

by Dmitry Nilov, Natalya Maluchenko, Tatyana Kurgina, Sergey Pushkarev, Alexandra Lys, Mikhail Kutuzov, Nadezhda Gerasimova, Alexey Feofanov, Vytas Švedas, Olga Lavrik and Vasily M. Studitsky

Int. J. Mol. Sci. 2020, 21(6), 2159; https://doi.org/10.3390/ijms21062159 - 20 Mar 2020

Cited by 20 | Viewed by 4194

Abstract

7-Methylguanine (7-MG), a natural compound that inhibits DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), can be considered as a potential anticancer drug candidate. Here we describe a study of 7-MG inhibition mechanism using molecular dynamics, fluorescence anisotropy and single-particle Förster resonance energy transfer [...] Read more.

7-Methylguanine (7-MG), a natural compound that inhibits DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP-1), can be considered as a potential anticancer drug candidate. Here we describe a study of 7-MG inhibition mechanism using molecular dynamics, fluorescence anisotropy and single-particle Förster resonance energy transfer (spFRET) microscopy approaches to elucidate intermolecular interactions between 7-MG, PARP-1 and nucleosomal DNA. It is shown that 7-MG competes with substrate NAD⁺ and its binding in the PARP-1 active site is mediated by hydrogen bonds and nonpolar interactions with the Gly863, Ala898, Ser904, and Tyr907 residues. 7-MG promotes formation of the PARP-1–nucleosome complexes and suppresses DNA-dependent PARP-1 automodification. This results in nonproductive trapping of PARP-1 on nucleosomes and likely prevents the removal of genotoxic DNA lesions. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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25 pages, 3047 KiB

Open AccessArticle

Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

by Yuliya V. Sherstyuk, Nikita V. Ivanisenko, Alexandra L. Zakharenko, Maria V. Sukhanova, Roman Y. Peshkov, Ilia V. Eltsov, Mikhail M. Kutuzov, Tatiana A. Kurgina, Ekaterina A. Belousova, Vladimir A. Ivanisenko, Olga I. Lavrik, Vladimir N. Silnikov and Tatyana V. Abramova

Int. J. Mol. Sci. 2020, 21(1), 214; https://doi.org/10.3390/ijms21010214 - 27 Dec 2019

Cited by 13 | Viewed by 4315

Abstract

We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP-ribose)polymerases-1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5-haloganeted pyrimidines, and mimicking a [...] Read more.

We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP-ribose)polymerases-1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5-haloganeted pyrimidines, and mimicking a main substrate of these enzymes, nicotinamide adenine dinucleotide (NAD+)-molecule, have been synthesized in a high yield. Morpholino nucleosides have been tethered to the β-phosphate of ADP via a phosphoester or phosphoramide bond. Screening of the inhibiting properties of these derivatives on the autopoly(ADP-ribosyl)ation of PARP-1 and PARP-2 has shown that the effect depends upon the type of nucleobase as well as on the linkage between ADP and morpholino nucleoside. The 5-iodination of uracil and the introduction of the P–N bond in NAD+-mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP-1 contained 5-iodouracil 2ʹ-aminomethylmorpholino nucleoside with IC50 126 ± 6 μM, while in the case of PARP-2 it was adenine 2ʹ-aminomethylmorpholino nucleoside (IC50 63 ± 10 μM). In silico analysis revealed that thymine and uracil-based NAD+ analogs were recognized as the NAD+-analog that targets the nicotinamide binding site. On the contrary, the adenine 2ʹ-aminomethylmorpholino nucleoside-based NAD+ analogs were predicted to identify as PAR-analogs that target the acceptor binding site of PARP-2, representing a novel molecular mechanism for selective PARP inhibition. This discovery opens a new avenue for the rational design of PARP-1/2 specific inhibitors. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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21 pages, 2803 KiB

Open AccessArticle

Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy

by Tatyana M. Khomenko, Alexandra L. Zakharenko, Arina A. Chepanova, Ekaterina S. Ilina, Olga D. Zakharova, Vasily I. Kaledin, Valeriy P. Nikolin, Nelly A. Popova, Dina V. Korchagina, Jóhannes Reynisson, Raina Chand, Daniel M. Ayine-Tora, Jinal Patel, Ivanhoe K. H. Leung, Konstantin P. Volcho, Nariman F. Salakhutdinov and Olga I. Lavrik

Int. J. Mol. Sci. 2020, 21(1), 126; https://doi.org/10.3390/ijms21010126 - 23 Dec 2019

Cited by 34 | Viewed by 4089

Abstract

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan [...] Read more.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is an important DNA repair enzyme in humans, and a current and promising inhibition target for the development of new chemosensitizing agents due to its ability to remove DNA damage caused by topoisomerase 1 (Top1) poisons such as topotecan and irinotecan. Herein, we report our work on the synthesis and characterization of new Tdp1 inhibitors that combine the arylcoumarin (neoflavonoid) and monoterpenoid moieties. Our results showed that they are potent Tdp1 inhibitors with IC₅₀ values in the submicromolar range. In vivo experiments with mice revealed that compound 3ba (IC₅₀ 0.62 µM) induced a significant increase in the antitumor effect of topotecan on the Krebs-2 ascites tumor model. Our results further strengthen the argument that Tdp1 is a druggable target with the potential to be developed into a clinically-potent adjunct therapy in conjunction with Top1 poisons. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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13 pages, 2096 KiB

Open AccessArticle

A Small Compound KJ-28d Enhances the Sensitivity of Non-Small Cell Lung Cancer to Radio- and Chemotherapy

by Hwani Ryu, Hyo Jeong Kim, Jie-Young Song, Sang-Gu Hwang, Jae-Sung Kim, Joon Kim, Thi Hong Nhung Bui, Hyun-Kyung Choi and Jiyeon Ahn

Int. J. Mol. Sci. 2019, 20(23), 6026; https://doi.org/10.3390/ijms20236026 - 29 Nov 2019

Cited by 8 | Viewed by 3358

Abstract

We previously reported on a poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor N-(3-(hydroxycarbamoyl)phenyl)carboxamide (designated KJ-28d), which increased the death of human ovarian cancer BRCA1-deficient SNU-251 cells. In the present study, we further investigated the antitumor activities of KJ-28d in BRCA-proficient non-small [...] Read more.

We previously reported on a poly (ADP-ribose) polymerase (PARP) 1/2 inhibitor N-(3-(hydroxycarbamoyl)phenyl)carboxamide (designated KJ-28d), which increased the death of human ovarian cancer BRCA1-deficient SNU-251 cells. In the present study, we further investigated the antitumor activities of KJ-28d in BRCA-proficient non-small cell lung cancer (NSCLC) cells to expand the use of PARP inhibitors. KJ-28d significantly inhibited the growth of NSCLC cells in vitro and in vivo, and induced DNA damage and reactive oxygen species in A549 and H1299 cells. Combined treatment with KJ-28d and ionizing radiation led to increased DNA damage responses in A549 and H1299 cells compared to KJ-28d or ionizing radiation alone, resulting in apoptotic cell death. Moreover, the combination of KJ-28d plus a DNA-damaging therapeutic agent (carboplatin, cisplatin, paclitaxel, or doxorubicin) synergistically inhibited cell proliferation, compared to either drug alone. Taken together, the findings demonstrate the potential of KJ-28d as an effective anti-cancer therapeutic agent for BRCA-deficient and -proficient cancer cells. KJ-28d might have potential as an adjuvant when used in combination with radiotherapy or DNA-damaging agents, pending further investigations. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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Review

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19 pages, 3301 KiB

Open AccessReview

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

by Natalya V. Maluchenko, Alexey V. Feofanov and Vasily M. Studitsky

Int. J. Mol. Sci. 2021, 22(21), 11441; https://doi.org/10.3390/ijms222111441 - 23 Oct 2021

Cited by 15 | Viewed by 4766

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, [...] Read more.

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. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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13 pages, 1035 KiB

Open AccessReview

Role of Nucleotide Excision Repair in Cisplatin Resistance

by Mingrui Duan, Jenna Ulibarri, Ke Jian Liu and Peng Mao

Int. J. Mol. Sci. 2020, 21(23), 9248; https://doi.org/10.3390/ijms21239248 - 4 Dec 2020

Cited by 52 | Viewed by 5195

Abstract

Cisplatin is a chemotherapeutic drug used for the treatment of a number of cancers. The efficacy of cisplatin relies on its binding to DNA and the induction of cytotoxic DNA damage to kill cancer cells. Cisplatin-based therapy is best known for curing testicular [...] Read more.

Cisplatin is a chemotherapeutic drug used for the treatment of a number of cancers. The efficacy of cisplatin relies on its binding to DNA and the induction of cytotoxic DNA damage to kill cancer cells. Cisplatin-based therapy is best known for curing testicular cancer; however, treatment of other solid tumors with cisplatin has not been as successful. Pre-clinical and clinical studies have revealed nucleotide excision repair (NER) as a major resistance mechanism against cisplatin in tumor cells. NER is a versatile DNA repair system targeting a wide range of helix-distorting DNA damage. The NER pathway consists of multiple steps, including damage recognition, pre-incision complex assembly, dual incision, and repair synthesis. NER proteins can recognize cisplatin-induced DNA damage and remove the damage from the genome, thereby neutralizing the cytotoxicity of cisplatin and causing drug resistance. Here, we review the molecular mechanism by which NER repairs cisplatin damage, focusing on the recent development of genome-wide cisplatin damage mapping methods. We also discuss how the expression and somatic mutations of key NER genes affect the response of cancer cells to cisplatin. Finally, small molecules targeting NER factors provide important tools to manipulate NER capacity in cancer cells. The status of research on these inhibitors and their implications in cancer treatment will be discussed. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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18 pages, 3345 KiB

Open AccessReview

Fused in Sarcoma (FUS) in DNA Repair: Tango with Poly(ADP-ribose) Polymerase 1 and Compartmentalisation of Damaged DNA

by Maria V. Sukhanova, Anastasia S. Singatulina, David Pastré and Olga I. Lavrik

Int. J. Mol. Sci. 2020, 21(19), 7020; https://doi.org/10.3390/ijms21197020 - 24 Sep 2020

Cited by 28 | Viewed by 4642

Abstract

The fused in sarcoma (FUS) protein combines prion-like properties with a multifunctional DNA/RNA-binding domain and has functions spanning the regulation of RNA metabolism, including transcription, pre-mRNA splicing, mRNA transport and translation. In addition to its roles in RNA metabolism, FUS is implicated in [...] Read more.

The fused in sarcoma (FUS) protein combines prion-like properties with a multifunctional DNA/RNA-binding domain and has functions spanning the regulation of RNA metabolism, including transcription, pre-mRNA splicing, mRNA transport and translation. In addition to its roles in RNA metabolism, FUS is implicated in the maintenance of DNA integrity. In this review, we examine the participation of FUS in major DNA repair pathways, focusing on DNA repair associated with poly(ADP-ribosyl)ation events and on how the interaction of FUS with poly(ADP-ribose) may orchestrate transient compartmentalisation of DNA strand breaks. Unravelling how prion-like RNA-binding proteins control DNA repair pathways will deepen our understanding of the pathogenesis of some neurological diseases and cancer as well as provide the basis for the development of relevant innovative therapeutic technologies. This knowledge may also extend the range of applications of poly(ADP-ribose) polymerase inhibitors to the treatment of neurodegenerative diseases related to RNA-binding proteins in the cell, e.g., amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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29 pages, 2178 KiB

Open AccessReview

Inhibition of DNA Repair in Cancer Therapy: Toward a Multi-Target Approach

by Samuele Lodovichi, Tiziana Cervelli, Achille Pellicioli and Alvaro Galli

Int. J. Mol. Sci. 2020, 21(18), 6684; https://doi.org/10.3390/ijms21186684 - 12 Sep 2020

Cited by 25 | Viewed by 5084

Abstract

Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we [...] Read more.

Alterations in DNA repair pathways are one of the main drivers of cancer insurgence. Nevertheless, cancer cells are more susceptible to DNA damage than normal cells and they rely on specific functional repair pathways to survive. Thanks to advances in genome sequencing, we now have a better idea of which genes are mutated in specific cancers and this prompted the development of inhibitors targeting DNA repair players involved in pathways essential for cancer cells survival. Currently, the pivotal concept is that combining the inhibition of mechanisms on which cancer cells viability depends is the most promising way to treat tumorigenesis. Numerous inhibitors have been developed and for many of them, efficacy has been demonstrated either alone or in combination with chemo or radiotherapy. In this review, we will analyze the principal pathways involved in cell cycle checkpoint and DNA repair focusing on how their alterations could predispose to cancer, then we will explore the inhibitors developed or in development specifically targeting different proteins involved in each pathway, underscoring the rationale behind their usage and how their combination and/or exploitation as adjuvants to classic therapies could help in patients clinical outcome. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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30 pages, 5124 KiB

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Inhibitors of DNA Glycosylases as Prospective Drugs

by Grigory V. Mechetin, Anton V. Endutkin, Evgeniia A. Diatlova and Dmitry O. Zharkov

Int. J. Mol. Sci. 2020, 21(9), 3118; https://doi.org/10.3390/ijms21093118 - 28 Apr 2020

Cited by 21 | Viewed by 4119

Abstract

DNA glycosylases are enzymes that initiate the base excision repair pathway, a major biochemical process that protects the genomes of all living organisms from intrinsically and environmentally inflicted damage. Recently, base excision repair inhibition proved to be a viable strategy for the therapy [...] Read more.

DNA glycosylases are enzymes that initiate the base excision repair pathway, a major biochemical process that protects the genomes of all living organisms from intrinsically and environmentally inflicted damage. Recently, base excision repair inhibition proved to be a viable strategy for the therapy of tumors that have lost alternative repair pathways, such as BRCA-deficient cancers sensitive to poly(ADP-ribose)polymerase inhibition. However, drugs targeting DNA glycosylases are still in development and so far have not advanced to clinical trials. In this review, we cover the attempts to validate DNA glycosylases as suitable targets for inhibition in the pharmacological treatment of cancer, neurodegenerative diseases, chronic inflammation, bacterial and viral infections. We discuss the glycosylase inhibitors described so far and survey the advances in the assays for DNA glycosylase reactions that may be used to screen pharmacological libraries for new active compounds. Full article

(This article belongs to the Special Issue Inhibition of DNA Repair Enzymes as a Valuable Pharmaceutical Approach)

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