Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer

Patnaik, Srinivas; Anupriya, -

doi:10.3389/fphar.2019.00588

Cited by 80 publications

(81 citation statements)

References 130 publications

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“…Frequently, these collaborator genes are not activated through genetic alterations, but by epigenetic mechanisms. In recent years, a number of studies suggested that drugs targeting epigenetic alterations could be applied in synergy with other anticancer therapies or, importantly, in reversing acquired therapy resistance (reviewed in [169,176,177,207,208]. However, due to the very limited tolerability of drugs targeting epigenetic mechanisms in combination with targeted therapies, most clinical trials have been disappointing so far.…”

Section: Targeting Histone Deacetylases (Hdacs)mentioning

confidence: 99%

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee

Rauch

Kölch

2020

IJMS

486

338

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Mitogen-activated protein kinase (MAPK) pathways represent ubiquitous signal transduction pathways that regulate all aspects of life and are frequently altered in disease. Here, we focus on the role of MAPK pathways in modulating drug sensitivity and resistance in cancer. We briefly discuss new findings in the extracellular signaling-regulated kinase (ERK) pathway, but mainly focus on the mechanisms how stress activated MAPK pathways, such as p38 MAPK and the Jun N-terminal kinases (JNK), impact the response of cancer cells to chemotherapies and targeted therapies. In this context, we also discuss the role of metabolic and epigenetic aberrations and new therapeutic opportunities arising from these changes.

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Section: Targeting Histone Deacetylases (Hdacs)mentioning

confidence: 99%

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Lee

Rauch

Kölch

2020

IJMS

486

338

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“…Despite tumour cell heterogeneity has been recognized as a bona fide engine for drug resistance [1, 3, 76], few successful approaches [17] have been proposed aimed at formulating strategies capable of quantifying the variability associated to individual cancer cell heterogeneity and minimizing its undesirable impact on clinical outcomes. Our current work accepts this challenge to provide a computational approach that allows the rational design of combinatorial therapies involving epigenetic drugs against cancer-driving chromatin modifiers [77–79].…”

Section: Resultsmentioning

confidence: 99%

Bivalent chromatin as a therapeutic target in cancer: Anin silicopredictive approach for combining epigenetic drugs

Alarcón

Sardanyés

Guillamón

et al. 2020

Preprint

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Tumour cell heterogeneity is a major barrier for efficient design of targeted anti-cancer therapies. A diverse distribution of phenotypically distinct tumour-cell subpopulations prior to drug treatment predisposes to non-uniform responses, leading to the elimination of sensitive cancer cells whilst leaving resistant subpopulations unharmed. Few strategies have been proposed for quantifying the variability associated to individual cancer-cell heterogeneity and minimizing its undesirable impact on clinical outcomes. Here, we report a computational approach that allows the rational design of combinatorial therapies involving epigenetic drugs against chromatin modifiers. We have formulated a stochastic model of a bivalent transcription factor that allows us to characterise three different qualitative behaviours, namely: bistable, high- and low-gene expression. Comparison between analytical results and experimental data determined that the so-called bistable and high-gene expression behaviours can be identified with undifferentiated and differentiated cell types, respectively. Since undifferentiated cells with an aberrant self-renewing potential might exhibit a cancer/metastasis-initiating phenotype, we analysed the efficiency of combining epigenetic drugs against the background of heterogeneity within the bistable sub-ensemble. Whereas single-targeted approaches mostly failed to circumvent the therapeutic problems represented by tumour heterogeneity, combinatorial strategies fared much better. Specifically, the more successful combinations were predicted to involve modulators of the histone H3K4 and H3K27 demethylases KDM5 and KDM6A/UTX. Those strategies involving the H3K4 and H3K27 methyltransferases MLL2 and EZH2, however, were predicted to be less effective. Our theoretical framework provides a coherent basis for the development of an in-silico platform capable of identifying the epigenetic drugs combinations best-suited to therapeutically manage non-uniform responses of heterogenous cancer cell populations.

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“…It is noteworthy that P. agglomerans C1 has genes encoding enzymes (e.g., a CAT-catalase, ec 1.11.1.6) that are involved in the biosynthesis of cinnamic-related compounds from intermediates of the tryptophan pathway, and we have evidence that strain C1 produces cinnamates as well as peptides and cyclopeptides that can crosstalk with auxin ( Luziatelli et al, 2020b ). These compounds may likely play a possible regulative role in plant gene expression through epigenetic mechanisms, such as DNA methylation, histone modification (acetylation, methylation, and phosphorylation), and miRNA activation, as it already emerged in humans ( Zhu et al, 2016 ; Frolinger et al 2018 ; Arora et al, 2019 ; Carlos-Reyes et al, 2019 ; Patnaik and Anupriya, 2019 ). These mechanisms likely activate many regulatory pathways generating a response, in parallel to the pathway activated by auxin compounds, and thus establish a synergistic action.…”

Section: Discussionmentioning

confidence: 99%

Metabolites Secreted by a Plant-Growth-Promoting Pantoea agglomerans Strain Improved Rooting of Pyrus communis L. cv Dar Gazi Cuttings

et al. 2020

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Strains belonging to Pantoea agglomerans species are known for their ability to produce metabolites that can act in synergy with auxins to induce the adventitious root (AR) formation. The latter is critically important in the agamic propagation of several woody species, including pear ( Pyrus communis L.), playing a considerable role in the commercial nursery farms including those using micropropagation techniques. When grown on a medium amended with tryptophan, the plant-growth-promoting (PGP) strain P. agglomerans C1 produces a cocktail of auxin and auxin-like molecules that can be utilized as biostimulants to improve the rooting of vegetable ( Solanum lycopersicum L.) and woody crop species ( Prunus rootstock GF/677 and hazelnut). In this study, we evaluated the morphological and molecular responses induced by strain C1 exometabolites in microcuttings of P. communis L. cv Dar Gazi and the potential benefits arising from their application. Results showed that exometabolites by P. agglomerans C1 induced a direct and earlier emergence of roots from stem tissues and determined modifications of root morphological parameters and root architecture compared to plants treated with the synthetic hormone indole-3-butyric acid (IBA). Transcription analysis revealed differences in the temporal expression pattern of ARF17 gene when IBA and C1 exometabolites were used alone, while together they also determined changes in the expression pattern of other key auxin-regulated plant genes. These results suggest that the phenotypic and molecular changes triggered by P. agglomerans C1 are dependent on different stimulatory and inhibitory effects that auxin-like molecules and other metabolites secreted by this strain have on the gene regulatory network of the plant. This evidence supports the hypothesis that the strategies used to harness the metabolic potential of PGP bacteria are key factors in obtaining novel biostimulants for sustainable agriculture. Our results demonstrate that metabolites secreted by strain C1 can be successfully used to increase the efficiency of micropropagation of pear through tissue culture techniques.

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Drugs Targeting Epigenetic Modifications and Plausible Therapeutic Strategies Against Colorectal Cancer

Cited by 80 publications

References 130 publications

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity

Bivalent chromatin as a therapeutic target in cancer: Anin silicopredictive approach for combining epigenetic drugs

Metabolites Secreted by a Plant-Growth-Promoting Pantoea agglomerans Strain Improved Rooting of Pyrus communis L. cv Dar Gazi Cuttings

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