CDK4 as a phytochemical based anticancer drug target

Mapping Intimacies ◽

10.1101/859595 ◽

2019 ◽

Author(s):

Rony Kumer Chando ◽

Nazmul Hussain ◽

Mashedul Islam Rana ◽

Shomoita Sayed ◽

Saruar Alam ◽

...

Keyword(s):

Medicinal Plants ◽

Anticancer Drug ◽

Drug Target ◽

Mangifera Indica ◽

Underlying Mechanism ◽

Lower Grade ◽

Active Compounds ◽

Mango Tree ◽

Lower Grade Glioma ◽

Based Medicine

AbstractSuccess story of plant-based medicine had been overlooked during the advent of modern pharmaceutical industry. Despite the negligence of the multimillion-dollar drug industry, people entirely rely on medicinal plants in some part of the world. In this study, we have emphasized on going back to those traditional medicinal practices to figure out their underlying mechanism to move forward on phytochemical based drug development. We screened Medicinal Plant Database Bangladesh 1.0 (MPDB1.0) and on-going extension, MPDB2.0, of that database to find traditionally used medicinal plants and their active compounds. Here, Mangiferin, extracted from Mangifera indica, have been demonstrated to interact with cell cycle regulator Cyclin-dependent Kinase 4 (CDK4). CDK4 is differentially expressed during Glioblastoma multiforme (GBM), Brain Lower Grade Glioma (LGG), and Sarcoma (SARC). Expression of CDK4 is interlinked to the patients’ survival rate and its consistent expression throughout different stages have provided the advantage to use it as diagnostic tool and drug target. Altogether, this study demonstrated that simple mango tree extracted active compounds, mangiferin, can work as potential anticancer drug and leveraging the recent advancement of sequencing and gene expression data can accelerate the phytochemical based drug discovery process.

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TRPM4 in Cancer—A New Potential Drug Target

Biomolecules ◽

10.3390/biom11020229 ◽

2021 ◽

Vol 11 (2) ◽

pp. 229

Author(s):

Anna Borgström ◽

Christine Peinelt ◽

Paulina Stokłosa

Keyword(s):

Anticancer Drug ◽

Drug Target ◽

Transient Receptor Potential ◽

Human Cancer ◽

Receptor Potential ◽

B Cell Lymphoma ◽

Underlying Mechanism ◽

Monovalent Cation ◽

Transient Receptor Potential Melastatin ◽

And Migration

Transient receptor potential melastatin 4 (TRPM4) is widely expressed in various organs and associated with cardiovascular and immune diseases. Lately, the interest in studies on TRPM4 in cancer has increased. Thus far, TRPM4 has been investigated in diffuse large B-cell lymphoma, prostate, colorectal, liver, breast, urinary bladder, cervical, and endometrial cancer. In several types of cancer TRPM4 is overexpressed and contributes to cancer hallmark functions such as increased proliferation and migration and cell cycle shift. Hence, TRPM4 is a potential prognostic cancer marker and a promising anticancer drug target candidate. Currently, the underlying mechanism by which TRPM4 contributes to cancer hallmark functions is under investigation. TRPM4 is a Ca2+-activated monovalent cation channel, and its ion conductivity can decrease intracellular Ca2+ signaling. Furthermore, TRPM4 can interact with different partner proteins. However, the lack of potent and specific TRPM4 inhibitors has delayed the investigations of TRPM4. In this review, we summarize the potential mechanisms of action and discuss new small molecule TRPM4 inhibitors, as well as the TRPM4 antibody, M4P. Additionally, we provide an overview of TRPM4 in human cancer and discuss TRPM4 as a diagnostic marker and anticancer drug target.

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Paradoxes of evidence-based medicine in lower-grade glioma

Neurology ◽

10.1212/wnl.0000000000006288 ◽

2018 ◽

Vol 91 (14) ◽

pp. 657-662 ◽

Cited By ~ 6

Author(s):

Hugues Duffau

Keyword(s):

Evidence Based Medicine ◽

Evidence Based ◽

Lower Grade ◽

Brain Organization ◽

Large Variability ◽

Individual Level ◽

Standardized Protocol ◽

Lower Grade Glioma ◽

The Individual ◽

Based Medicine

Brain lower-grade gliomas (LGG) usually occur in young adults who enjoy an active life. This tumor has a high risk of malignant transformation resulting in neurologic deterioration and finally death. Early and multistage therapeutic management can increase survival over 10 years. Preservation of functional neural networks and quality of life is crucial. In the era of evidence-based medicine, the issues discussed are those associated with the design, analysis, and clinical application of randomized controlled trials (RCTs) for LGG. RCTs should take account of the following: considerable variability in the natural course of LGG; limited prognostic value of molecular biology at the individual level; large variability of brain organization across patients; technical and conceptual progress of therapies over years; combination or repetition of iterative treatments, taken as a whole and not only in isolation; and long-term consequences on oncologic and functional outcomes. As it is difficult to translate the results of an RCT into benefits for a unique patient with LGG, personalized decisions must be made by considering the tumor behavior, individual pattern of neuroplasticity, and patient needs, and not by administrating a standardized protocol exclusively based on an RCT.

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RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

Scientific Reports ◽

10.1038/s41598-021-91382-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Haiwei Wang ◽

Xinrui Wang ◽

Liangpu Xu ◽

Ji Zhang ◽

Hua Cao

Keyword(s):

Transcription Factor ◽

Low Frequency ◽

Tumor Grade ◽

The Cancer Genome Atlas ◽

Lower Grade ◽

Wild Type ◽

Lower Grade Glioma ◽

Cancer Genome Atlas ◽

Worse Prognosis ◽

Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

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Identification of anticancer drug target genes using an outside competitive dynamics model on cancer signaling networks

Scientific Reports ◽

10.1038/s41598-021-93336-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tien-Dzung Tran ◽

Duc-Tinh Pham

Keyword(s):

Anticancer Drug ◽

Drug Target ◽

Target Genes ◽

Signaling Network ◽

Competitive Dynamics ◽

Signaling Networks ◽

Molecular Signaling ◽

Dynamics Model ◽

Cancer Signaling ◽

The Impact

AbstractEach cancer type has its own molecular signaling network. Analyzing the dynamics of molecular signaling networks can provide useful information for identifying drug target genes. In the present study, we consider an on-network dynamics model—the outside competitive dynamics model—wherein an inside leader and an opponent competitor outside the system have fixed and different states, and each normal agent adjusts its state according to a distributed consensus protocol. If any normal agent links to the external competitor, the state of each normal agent will converge to a stable value, indicating support to the leader against the impact of the competitor. We determined the total support of normal agents to each leader in various networks and observed that the total support correlates with hierarchical closeness, which identifies biomarker genes in a cancer signaling network. Of note, by experimenting on 17 cancer signaling networks from the KEGG database, we observed that 82% of the genes among the top 3 agents with the highest total support are anticancer drug target genes. This result outperforms those of four previous prediction methods of common cancer drug targets. Our study indicates that driver agents with high support from the other agents against the impact of the external opponent agent are most likely to be anticancer drug target genes.

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QOLP-37. QUALITATIVE RESEARCH IN LOWER GRADE GLIOMA: UNDERSTANDING SIGNS, SYMPTOMS, AND DISEASE IMPACTS DURING EXPECTANT MANAGEMENT

Neuro-Oncology ◽

10.1093/neuonc/noz175.857 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi206-vi206

Author(s):

Audra Boscoe ◽

Ted Wells ◽

Christina Graham ◽

Caitlin Pohl ◽

Brooke Witherspoon ◽

...

Keyword(s):

Treatment Options ◽

Expectant Management ◽

Signs And Symptoms ◽

Molecular Therapy ◽

Patient Specific ◽

Lower Grade ◽

Concept Elicitation ◽

Post Surgery ◽

Lower Grade Glioma ◽

Isocitrate Dehydrogenase Mutation

Abstract BACKGROUND Patients with lower grade glioma (LGG) (i.e., grade II or III) have limited treatment options. After surgical resection of their tumor, patients will undergo either a period of expectant management (watch and wait) or treatment with adjuvant chemotherapy and/or radiotherapy. Approximately 80% of patients with LGG have an isocitrate dehydrogenase mutation, which is a viable target for molecular therapy. This offers a therapeutic intervention that could potentially delay the need for chemotherapy and/or radiotherapy in select patients. Several prognostic and patient-specific factors contribute to the decision to recommend expectant management, including concerns about the side effects of chemotherapy and radiotherapy. The aim of this project was to understand patients’ signs and symptoms during the expectant management period and how LGG impacts their lives. METHODS Concept elicitation interviews were conducted in the US with patients with LGG as well as key opinion leaders (KOLs) with experience treating patients with LGG. Interview data were analyzed using Atlas.ti, and patient data were reviewed against KOL data. RESULTS Seven patients with ≥ 3 months of expectant management experience and three KOLs were interviewed. During their expectant management periods, patients reported 12 signs/symptoms, mostly related to deficits in cognition. Patients reported 16 impacts across four categories, with a substantial proportion of the impacts identified as negatively affecting emotional function. The signs/symptoms and impacts reported by patients were generally also reported by KOLs. During expectant management, patients typically resume their original quality of life post-surgery, but may also experience anxiety. Patients and KOLs indicated a preference for expectant management and delaying chemotherapy or radiotherapy. CONCLUSIONS Patient and KOL interviews characterized the LGG experience and indicated a preference for expectant management, which may be supported by therapies that delay the initiation of chemotherapy and/or radiotherapy.

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Identification and Validation of an Individualized Prognostic Signature of Lower-Grade Glioma Based on Nine Immune Related Long Non-coding RNA

Clinical Neurology and Neurosurgery ◽

10.1016/j.clineuro.2020.106464 ◽

2021 ◽

pp. 106464

Author(s):

Aierpati Maimaiti ◽

Lei Jiang ◽

Xixian Wang ◽

Xin Shi ◽

Yinan Pei ◽

...

Keyword(s):

Lower Grade ◽

Prognostic Signature ◽

Non Coding Rna ◽

Lower Grade Glioma ◽

Long Non Coding Rna

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Prediction of Anti-COVID 19 Therapeutic Power of Medicinal Moroccan Plants Using Molecular Docking

Bioinformatics and Biology Insights ◽

10.1177/11779322211009199 ◽

2021 ◽

Vol 15 ◽

pp. 117793222110091

Author(s):

Badreddine Nouadi ◽

Abdelkarim Ezaouine ◽

Mariame El Messal ◽

Mohamed Blaghen ◽

Faiza Bennis ◽

...

Keyword(s):

Molecular Docking ◽

Medicinal Plants ◽

Drug Target ◽

Cost Effective ◽

Current Medical Research ◽

New Drugs ◽

Binding Affinities ◽

Global Public Health ◽

Public Health Challenge ◽

Ucsf Chimera

The emerging pathogen SARS-CoV2 causing coronavirus disease 2019 (COVID-19) is a global public health challenge. To the present day, COVID-19 had affected more than 40 million people worldwide. The exploration and the development of new bioactive compounds with cost-effective and specific anti-COVID 19 therapeutic power is the prime focus of the current medical research. Thus, the exploitation of the molecular docking technique has become essential in the discovery and development of new drugs, to better understand drug-target interactions in their original environment. This work consists of studying the binding affinity and the type of interactions, through molecular docking, between 54 compounds from Moroccan medicinal plants, dextran sulfate and heparin (compounds not derived from medicinal plants), and 3CLpro-SARS-CoV-2, ACE2, and the post fusion core of 2019-nCoV S2 subunit. The PDB files of the target proteins and prepared herbal compounds (ligands) were subjected for docking to AutoDock Vina using UCSF Chimera, which provides a list of potential complexes based on the criteria of form complementarity of the natural compound with their binding affinities. The results of molecular docking revealed that Taxol, Rutin, Genkwanine, and Luteolin-glucoside have a high affinity with ACE2 and 3CLpro. Therefore, these natural compounds can have 2 effects at once, inhibiting 3CLpro and preventing recognition between the virus and ACE2. These compounds may have a potential therapeutic effect against SARS-CoV2, and therefore natural anti-COVID-19 compounds.

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Epidermal growth factor receptor as a major anticancer drug target

Expert Opinion on Therapeutic Targets ◽

10.1517/14728222.10.6.877 ◽

2006 ◽

Vol 10 (6) ◽

pp. 877-888 ◽

Cited By ~ 6

Author(s):

Francesco Caponigro ◽

Amalia Milano ◽

Alessandro Ottaiano ◽

Rosario Vincenzo Iaffaioli

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Anticancer Drug ◽

Drug Target ◽

Growth Factor Receptor ◽

Epidermal Growth

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The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued

Neurosurgery ◽

10.1093/neuros/nyab052 ◽

2021 ◽

Author(s):

Peng Wang ◽

Chen Luo ◽

Peng-jie Hong ◽

Wen-ting Rui ◽

Shuai Wu

Keyword(s):

Cox Regression ◽

Progression Free Survival ◽

Extent Of Resection ◽

Lower Grade ◽

Wild Type ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Lower Grade Glioma ◽

Clinical Benefits

Abstract BACKGROUND While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

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