A Comprehensive Look of Poly(Adp-Ribose) Polymerase Inhibition Strategies and Future Directions for Cancer Therapy

Kumar, Chandan; Rani, Nidhi; Lakshmi, P.T.V.; Arunachalam, Annamalai

doi:10.4155/fmc-2016-0113

Cited by 14 publications

(17 citation statements)

References 155 publications

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“…Currently, several PARP-inhibitors are utilized in phase I and II clinical trials as mono or combination therapies in many human cancers including PCa [ 38 ]. To explore the role of PARP-1 in CRPC proliferation, we treated our cell lines with two PARP1-inhibitors: ABT-888, a PARP catalytic inhibitor [ 39 ] and BSI-201, a drug that disrupts the interaction between PARP-1 and DNA [ 40 ]. The results, reported in the Additional file 1 : Figure S4, show that ABT-888 inhibited LNCaP cell line and only partially MDB, while BSI-201 selectively affected PDB and MDB growth in a dose-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

et al. 2017

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BackgroundProstate cancer (PCa), the second most common cancer affecting men worldwide, shows a broad spectrum of biological and clinical behaviour representing the epiphenomenon of an extreme heterogeneity. Androgen deprivation therapy is the mainstay of treatment for advanced forms but after few years the majority of patients progress to castration-resistant prostate cancer (CRPC), a lethal form that poses considerable therapeutic challenges.MethodsWestern blotting, immunocytochemistry, invasion and reporter assays, and in vivo studies were performed to characterize androgen resistant sublines phenotype in comparison to the parental cell line LNCaP. RNA microarray, mass spectrometry, integrative transcriptomic and proteomic differential analysis coupled with GeneOntology and multivariate analyses were applied to identify deregulated genes and proteins involved in CRPC evolution.ResultsTreating the androgen-responsive LNCaP cell line for over a year with 10 μM bicalutamide both in the presence and absence of 0.1 nM 5-α-dihydrotestosterone (DHT) we obtained two cell sublines, designated PDB and MDB respectively, presenting several analogies with CRPC. Molecular and functional analyses of PDB and MDB, compared to the parental cell line, showed that both resistant cell lines were PSA low/negative with comparable levels of nuclear androgen receptor devoid of activity due to altered phosphorylation; cell growth and survival were dependent on AKT and p38MAPK activation and PARP-1 overexpression; their malignant phenotype increased both in vitro and in vivo. Performing bioinformatic analyses we highlighted biological processes related to environmental and stress adaptation supporting cell survival and growth. We identified 15 proteins that could direct androgen-resistance acquisition. Eleven out of these 15 proteins were closely related to biological processes involved in PCa progression.ConclusionsOur models suggest that environmental factors and epigenetic modulation can activate processes of phenotypic adaptation driving drug-resistance. The identified key proteins of these adaptive phenotypes could be eligible targets for innovative therapies as well as molecules of prognostic and predictive value.Electronic supplementary materialThe online version of this article (10.1186/s12964-017-0206-x) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

et al. 2017

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“…Among these sensitive drugs, gemcitabine, cytarabine, and clofarabine inhibited ribonucleotide reductase, leading to replication stress [28]. Olaparib, a poly ADP-Ribose polymerase 1 (PARP1) inhibitor, inhibited DNA repair [29]. The WEE1 inhibitor, MK-1775, induced premature CDK1 activation and abrogated G2 DNA damage checkpoint [30].…”

Section: Resultsmentioning

confidence: 99%

Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma

Hsieh

Liu

Chou

et al. 2019

Genes

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Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer. The five-year survival rate of PDAC is very low (less than 8%), which is associated with the late diagnosis, high metastatic potential, and resistance to therapeutic agents. The identification of better prognostic or therapeutic biomarker may have clinical benefits for PDAC treatment. SMAD4, a central mediator of transforming growth factor beta (TGFβ) signaling pathway, is considered a tumor suppressor gene. SMAD4 inactivation is frequently found in PDAC. However, its role in prognosis and therapeutics of PDAC is still unclear. In this study, we applied bioinformatics approaches, and integrated publicly available resources, to investigate the role of SMAD4 gene deletion in PDAC. We found that SMAD4 deletion was associated with poorer disease-free, but not overall, survival in PDAC patients. Cancer hallmark enrichment and pathway analysis suggested that the upregulation of cell cycle-related genes in SMAD4-deleted PDAC. Chemotherapy response profiling of PDAC cell lines and patient-derived organoids revealed that SMAD4-deleted PDAC was sensitive to gemcitabine, the first-line treatment for PDAC, and specific cell cycle-targeting drugs. Taken together, our study provides an insight into the prognostic and therapeutic roles of SMAD4 gene deletion in PDAC, and SMAD4 gene copy numbers may be used as a therapeutic biomarker for PDAC treatment.

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“…Because of its crucial role in mitosis and cancer, ARTD1 has been at the front line of drug discovery since the 1980s, and the first clinical trial for an ARTD1 inhibitor was initiated in 2003 with rucaparib [99]. Since then, other further inhibitors have entered clinical trials with the aim of blocking the mechanism of repair of damaged DNA through ARTD1 inhibition, and thus enhancing the DNA damage caused by chemotherapy and radiotherapy [11,15,16,19]. Currently, several PARP inhibitors such as olaparib, niraparib, talazoparib, veliparib, and the same rucaparib are under clinical trials [19].…”

Section: The Poly-artds: (Artd1 To Artd6)mentioning

confidence: 99%

“…PARP1 is the founding member of the PARP family and, for many years, it was the only PARP enzyme known. PARP1 is activated by DNA strand breaks, and its role in the cellular response to genotoxic and oxidative stress has been widely recognized and studied, with some PARP inhibitors being evaluated in several clinical trials as anticancer therapeutics [8][9][10][11][12][13][14][15][16][17]. Olaparib was the first PARP inhibitor to be used for the therapy of patients with ovarian tumors and, more recently, it has been approved by US Food and Drug Administration (FDA) for the treatments of this type of cancer [18].…”

Section: Introductionmentioning

confidence: 99%

The ADP-Ribosyl-Transferases Diphtheria Toxin-Like (ARTDs) Family: An Overview

Girolamo¹,

Fabrizio²

2018

Challenges

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Poly-ADP-ribosylation is a post-translational modification that occurs in multicellular organisms, including plants and some lower unicellular eukaryotes. The founding member of the PARP family is PARP1. To date, 17 members of the PARP family have been identified, which differ from each other in terms of domain organization, transmodification targets, cellular localization, and biological functions. In recent years, considering structural and biochemical features of the different members of the PARP family, a new classification has been proposed. Thus, enzymes firstly classified as PARP are now named diphtheria-toxin-like ARTs, abbreviated to ARTDs, in accordance with the prototype bacterial toxin that their structural aspects resemble, with numbers indicating the different proteins of the family. The 17 human ARTD enzymes can be divided on the basis of their catalytic activity into polymerases (ARTD1-6), mono-ADP-ribosyl-transferases (ARTD7-17), and the inactive ARTD13. In recent years, ADP-ribosylation was intensively studied, and research was dominated by studies focusing on the role of this modification and its implication on various cellular processes. The aim of this review is to provide a general overview of the ARTD enzymes, with a special focus on mono-ARTDs.

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A Comprehensive Look of Poly(Adp-Ribose) Polymerase Inhibition Strategies and Future Directions for Cancer Therapy

Cited by 14 publications

References 155 publications

Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

Adaptive phenotype drives resistance to androgen deprivation therapy in prostate cancer

Integration of Bioinformatics Resources Reveals the Therapeutic Benefits of Gemcitabine and Cell Cycle Intervention in SMAD4-Deleted Pancreatic Ductal Adenocarcinoma

The ADP-Ribosyl-Transferases Diphtheria Toxin-Like (ARTDs) Family: An Overview

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