PARP1 Inhibitors: Antitumor Drug Design Creative Commons

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Malyuchenko N.V.,

Kotova E.Y.,

Kulaeva O.I.,

Kirpichnikov M.P.,

Studitskiy V.M

ACTA NATURAE, Journal Year: 2015, Volume and Issue: 7(3), P. 27 - 37, https://doi.org/10.32607/20758251-2015-7-3-27-37

Published: Jan. 1, 2015

Latest article update: Sept. 26, 2022

The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1-2 million molecules per cell) serving as a “sensor” for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional …

Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression DOI Creative Commons
Zhi-Jie Liang, Yan Wan, Dandan Zhu

et al.

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: Feb. 25, 2021

Resveratrol (RSV) is known to possess anticancer properties in many types of cancers like breast cancer, which POLD1 may serve as a potential target. However, the mechanism RSV on triple negative cancer (TNBC) remains unclear. In present study, antitumor effects and TNBC cells were analyzed by RNA sequencing (RNA-seq), was then verified via cell counting kit-8 (CCK8), immunofluorescence, immunohistochemistry, Western Blot (WB), flow cytometry, hematoxylin-eosin (HE) staining. According corresponding findings, survival rate MDA-MB-231 gradually decreased treatment concentration increased. The RNA-seq analysis results demonstrated that genes affected mainly involved apoptosis p53 signaling pathway. Moreover, induced observed be mediated POLD1. When treated with RSV, expression levels full length PARP1, PCNA, BCL-2 found significantly reduced, level Cleaved-PARP1 well Cleaved-Caspase3 increased significantly. Additionally, mRNA reduced after protein also inhibited concentration-dependent manner. prediction domain interaction suggested bind at least five functional domains (6s1m, 6s1n, 6s1o, 6tny 6tnz). Furthermore, treatment, anti-apoptotic index (PCNA, BCL-2) decrease while (caspase3) overexpression extent following treatment. animal experimental showed had significant inhibitory effect growth live tumors, shown antagonize this effect. Accordingly, study’s findings reveal promote reducing activate apoptotic pathway, therapy for TNBC.

Language: Английский

Citations

49
Circadian Synchrony: Sleep, Nutrition, and Physical Activity DOI Creative Commons

Kelly L. Healy,

Andrew R. Morris, Andrew C. Liu

et al.

Frontiers in Network Physiology, Journal Year: 2021, Volume and Issue: 1

Published: Oct. 12, 2021

The circadian clock in mammals regulates the sleep/wake cycle and many associated behavioral physiological processes. cellular mechanism involves a transcriptional negative feedback loop that gives rise to rhythms gene expression with an approximately 24-h periodicity. To maintain system robustness, clocks throughout body must be synchronized their functions coordinated. In mammals, master is located suprachiasmatic nucleus (SCN) of hypothalamus. SCN entrained light/dark through photic signal transduction subsequent induction core expression. turn relays time-of-day information peripheral tissues. While highly responsive cues, are more sensitive non-photic resetting cues such as nutrients, temperature, neuroendocrine hormones. For example, feeding/fasting physical activity can entrain signaling pathways regulation genes proteins. As such, timing food intake matters. ideal world, cycles cycle. However, asynchronous environmental those experienced by shift workers frequent travelers, often lead misalignment between clocks. Emerging evidence suggests resulting disruption various diseases chronic conditions cause further desynchrony accelerate disease progression. this review, we discuss how sleep, nutrition, synchronize chronomedicine may offer novel strategies for intervention.

Language: Английский

Citations

43
Poly(ADP-Ribose) Polymerase (PARP) Inhibitors for Cancer Therapy: Advances, Challenges, and Future Directions DOI Creative Commons
Denys Bondar, Yevgen Karpichev

Biomolecules, Journal Year: 2024, Volume and Issue: 14(10), P. 1269 - 1269

Published: Oct. 9, 2024

Poly(ADP-ribose) polymerases (PARPs) are crucial nuclear proteins that play important roles in various cellular processes, including DNA repair, gene transcription, and cell death. Among the 17 identified PARP family members, PARP1 is most abundant enzyme, with approximately 1-2 million molecules per cell, acting primarily as a damage sensor. It has become promising biological target for anticancer drug studies. Enhanced expression present several types of tumors, such melanomas, lung cancers, breast correlating low survival outcomes resistance to treatment. inhibitors, especially newly developed third-generation inhibitors currently undergoing Phase II clinical trials, have shown efficacy agents both single drugs sensitizers chemo- radiotherapy. This review explores properties, characteristics, challenges discussing their development from first-generation compounds, more sustainable synthesis methods discovery new anti-cancer agents, mechanisms therapeutic action, potential targeting additional targets beyond catalytic active site proteins. Perspectives on green chemistry also discussed.

Language: Английский

Citations

7
PARP1expression and its correlation with survival is tumour molecular subtype dependent in glioblastoma DOI Open Access
Balázs Murnyák,

Mahan C. Kouhsari,

Rotem Hershkovitch

et al.

Oncotarget, Journal Year: 2017, Volume and Issue: 8(28), P. 46348 - 46362

Published: May 19, 2017

Overexpression of PARP1 exists in various cancers, including glioblastoma (GBM). Although inhibition is a promising therapeutic target, no comprehensive study has addressed PARP1's expression characteristics and prognostic role regarding molecular heterogeneity astrocytomas GBM. Our aim was to evaluate associations with survival, WHO grade, lineage specific markers, GBM transcriptomic subtypes. We collected genomic clinical data from the latest glioma datasets The Cancer Genome Atlas performed PARP1, ATRX, IDH1, p53 immunohistochemistry on tissue samples. demonstrated that gain increased mRNA are high-grade astrocytomas, particularly Proneural Classical Additionally, higher levels exhibited an inverse correlation patient survival (p<0.005) subgroup. ATRX (p=0.006), TP53 (p=0.015) mutations were associated protein level correlated loss overexpression. Furthermore, together wildtype indicated shorter (p=0.039). Therefore, due subtype specificity, mutation status reliable marker candidates distinguish subtypes, implications

Language: Английский

Citations

54
PARP-1-Associated Pathological Processes: Inhibition by Natural Polyphenols DOI Open Access

Natalya Maluchenko,

Alexey V. Feofanov, Vasily M. Studitsky

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(21), P. 11441 - 11441

Published: Oct. 23, 2021

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

Language: Английский

Citations

33
A critical review of benzimidazole: Sky-high objectives towards the lead molecule to predict the future in medicinal chemistry DOI Creative Commons
Sabyasachi Banerjee, Sougata Mukherjee,

Priyobrata Nath

et al.

Results in Chemistry, Journal Year: 2023, Volume and Issue: 6, P. 101013 - 101013

Published: June 23, 2023

Out of several heterocyclic templates, the use a Benzimidazole (BZ) scaffold is immensely observed. This fused heterocycle comprises two ring nitrogen atoms placed at 1st and 3rd position, in which connected to hydrogen that gets released exhibit acidic property. The BZ for purpose making clinically useful compounds was started year 1944. derivatives have been consistently used as effective chemotherapeutic agents treat diverse range disorders. Apart from their clinical usefulness, BZ-based also confer high safety, bio-availability, stability. conditions, cancer, helminthiasis are few where this template has maximally utilized. present review emphasizes chronologically developments entire scope medicinal chemistry antibacterial, anticancer, antifungal, anti-inflammatory, anti-HIV (human immunodeficiency virus), anticonvulsant, antioxidant, antidiabetic, antitubercular, antileishmanial, antimalarial, anti-histaminic. covers patents on importance till 2020. primary objective develop comprehensive SAR (structure–activity relationship), turn assists chemist come up with novel ideas, while being implemented could produce enormous potential.

Language: Английский

Citations

14
Role of PARP-1 structural and functional features in PARP-1 inhibitors development DOI

Alexander Vladimirovich Merkuryev,

Egorov Vv

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 156, P. 108188 - 108188

Published: Jan. 21, 2025

Language: Английский

Citations

0
PARP1: A comprehensive review of its mechanisms, therapeutic implications and emerging cancer treatments DOI Creative Commons
Carlota J.F. Conceição, Elin Moe, Paulo A. Ribeiro

et al.

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2025, Volume and Issue: unknown, P. 189282 - 189282

Published: Feb. 1, 2025

Language: Английский

Citations

0
Liquid‒liquid phase separation and poly(ADP‒ribosyl)ation in the context of ultraviolet radiation-induced stress in mammalian cells DOI

Daniela Mejías,

Valentina Seballos, Laura Lafon-Hughes

et al.

Biophysical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

Language: Английский

Citations

0
Reduction of metastatic potential by inhibiting EGFR/Akt/p38/ERK signaling pathway and epithelial-mesenchymal transition after carbon ion exposure is potentiated by PARP-1 inhibition in non-small-cell lung cancer DOI Creative Commons
Priyanka Chowdhury,

Payel Dey,

Sourav Ghosh

et al.

BMC Cancer, Journal Year: 2019, Volume and Issue: 19(1)

Published: Aug. 22, 2019

Carbon ion (12C) radiotherapy is becoming very promising to kill highly metastatic cancer cells keeping adjacent normal least affected. Our previous study shows that combined PARP-1 inhibition with 12C reduces MMP-2,-9 synergistically in HeLa but detailed mechanism are not clear. To understand this and the rationale of using inhibitor for better outcome controlling metastasis, we investigated potential two non-small cell lung (NSCLC) A549 H1299 (p53-deficient) exposed presence absence siRNA or olaparib.We monitored proliferation, in-vitro migration, wound healing, expression activity MMP-2, - 9 p53-deficient lines without olaparib/DPQ. Expression phosphorylation NF-kB, EGFR, Akt, p38, ERK was also observed olaparib. We checked few marker genes involved epithelial-mesenchymal transition (EMT) pathways like N-cadherin, vimentin, anillin, claudin-1, 2 both NSCLC. determine generalized effect olaparib cell's potential, healing studied MCF7 after exposure combination olaparib.Our experiments show separately resulting inactivation NF-kB. Combined treatment abolishes NF-kB hence expressions. Each single anillin increases leading suppression EMT process. However, alters these proteins suppress significantly.The activation transcription via key targeted by olaparib/siRNA. Hence, could potentially be as chemotherapeutic agent control metastasis.

Language: Английский

Citations

38