scholarly journals Drug target ranking for glioblastoma multiforme

2021 ◽  
Vol 3 (1) ◽  
Author(s):  
Radhika Saraf ◽  
Shaghayegh Agah ◽  
Aniruddha Datta ◽  
Xiaoqian Jiang
Keyword(s):  
Brain Tumor ◽  
Glioblastoma Multiforme ◽  
Boolean Network ◽  
Drug Repurposing ◽  
Boolean Model ◽  
Chemotherapeutic Agents ◽  
Drug Combinations ◽  
Cancer Drug ◽  
Genetic Profile ◽  
Cancer Drugs

Abstract Background Glioblastoma Multiforme, an aggressive primary brain tumor, has a poor prognosis and no effective standard of care treatments. Most patients undergoing radiotherapy, along with Temozolomide chemotherapy, develop resistance to the drug, and recurrence of the tumor is a common issue after the treatment. We propose to model the pathways active in Glioblastoma using Boolean network techniques. The network captures the genetic interactions and possible mutations that are involved in the development of the brain tumor. The model is used to predict the theoretical efficacies of drugs for the treatment of cancer. Results We use the Boolean network to rank the critical intervention points in the pathway to predict an effective therapeutic strategy for Glioblastoma. Drug repurposing helps to identify non-cancer drugs that could be effective in cancer treatment. We predict the effectiveness of drug combinations of anti-cancer and non-cancer drugs for Glioblastoma. Conclusions Given the genetic profile of a GBM tumor, the Boolean model can predict the most effective targets for treatment. We also identified two-drug combinations that could be more effective in killing GBM cells than conventional chemotherapeutic agents. The non-cancer drug Aspirin could potentially increase the cytotoxicity of TMZ in GBM patients.

scholarly journals Predicting and Quantifying Antagonistic Effects of Natural Compounds Given with Chemotherapeutic Agents: Applications for High-Throughput Screening

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3714
Author(s):  
G. Lavender Hackman ◽  
Meghan Collins ◽  
Xiyuan Lu ◽  
Alessia Lodi ◽  
John DiGiovanni ◽  
...  
Keyword(s):  
Natural Products ◽  
High Throughput ◽  
High Throughput Screening ◽  
Cancer Therapeutics ◽  
Chemotherapeutic Agents ◽  
The Body ◽  
Cancer Drug ◽  
Therapeutic Effects ◽  
Cancer Drugs ◽  
Antagonistic Effects

Natural products have been used for centuries to treat various human ailments. In recent decades, multi-drug combinations that utilize natural products to synergistically enhance the therapeutic effects of cancer drugs have been identified and have shown success in improving treatment outcomes. While drug synergy research is a burgeoning field, there are disagreements on the definitions and mathematical parameters that prevent the standardization and proper usage of the terms synergy, antagonism, and additivity. This contributes to the relatively small amount of data on the antagonistic effects of natural products on cancer drugs that can diminish their therapeutic efficacy and prevent cancer regression. The ability of natural products to potentially degrade or reverse the molecular activity of cancer therapeutics represents an important but highly under-emphasized area of research that is often overlooked in both pre-clinical and clinical studies. This review aims to evaluate the body of work surrounding the antagonistic interactions between natural products and cancer therapeutics and highlight applications for high-throughput screening (HTS) and deep learning techniques for the identification of natural products that antagonize cancer drug efficacy.

scholarly journals EXTH-72. MANZAMINE A-DERIVED COMPOUNDS AS POTENTIAL ANTI-BRAIN TUMOR AGENTS AND IT MECHANISM STUDY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi97-vi97
Author(s):  
Chiung-Yin Huang ◽  
Pin-Yuan Chen ◽  
Kuo-Chen Wei ◽  
Tsong-Long Hwang
Keyword(s):  
Brain Tumor ◽  
Tumor Cells ◽  
Severe Disease ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Optimal Dosage ◽  
Target Area ◽  
Mechanism Study ◽  
Anticancer Activities ◽  
Manzamine A

Abstract Glioma is a severe disease with poor prognosis. Chemotherapy plays an important role but very few drugs are effective. There are two major issues: (1) the specialized blood-brain barrier blocks most large molecules from penetrating into target area; (2) tumor cells frequently develop drug resistant. Therefore, developing new chemotherapeutic agents for malignant brain tumor treatment may significantly improve the current difficulties. Compounds derived from nature products have been considered as potential sources for new discovery of anti-cancer drug. Manzamine A-derived compounds, showed significant anticancer activities against colon adenocarcinoma DLD cells, lung large cell carcinoma NCI-H661 cells, and hepatoma HepG2/A2 cells. In this study, we used in vitro model for screening these compounds and discovered both cytotoxic and anti-proliferative effects against brain tumor cells, such as A172, U87MG, and GL261 cell lines. We then used animal models to test the toxicities and treatment effect of compound A3 in vivo, and delivered the agent by convection-enhanced delivery to improve drug concentration in brain. Survival benefit for brain tumor-bearing animal was found for optimal dosage of compound A3. Details of anti-tumor mechanism need further evaluation.

scholarly journals Anti-Cancer Agents in Proliferation and Cell Death: The Calcium Connection

2019 ◽  
Vol 20 (12) ◽  
pp. 3017 ◽  
Author(s):  
Elizabeth Varghese ◽  
Samson Mathews Samuel ◽  
Zuhair Sadiq ◽  
Peter Kubatka ◽  
Alena Liskova ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Calcium Signaling ◽  
Drug Targets ◽  
Epigenetic Modification ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Cellular Survival ◽  
Anti Cancer

Calcium (Ca2+) signaling and the modulation of intracellular calcium ([Ca2+]i) levels play critical roles in several key processes that regulate cellular survival, growth, differentiation, metabolism, and death in normal cells. On the other hand, aberrant Ca2+-signaling and loss of [Ca2+]i homeostasis contributes to tumor initiation proliferation, angiogenesis, and other key processes that support tumor progression in several different cancers. Currently, chemically and functionally distinct drugs are used as chemotherapeutic agents in the treatment and management of cancer among which certain anti-cancer drugs reportedly suppress pro-survival signals and activate pro-apoptotic signaling through modulation of Ca2+-signaling-dependent mechanisms. Most importantly, the modulation of [Ca2+]i levels via the endoplasmic reticulum-mitochondrial axis and corresponding action of channels and pumps within the plasma membrane play an important role in the survival and death of cancer cells. The endoplasmic reticulum-mitochondrial axis is of prime importance when considering Ca2+-signaling-dependent anti-cancer drug targets. This review discusses how calcium signaling is targeted by anti-cancer drugs and highlights the role of calcium signaling in epigenetic modification and the Warburg effect in tumorigenesis.

GLIOBLASTOMA MULTIFORME: PATHOGENESIS AND MOLECULAR MARKERS

2017 ◽  
Vol 63 (5) ◽  
pp. 695-702
Author(s):  
Oleg Kit ◽  
Dmitriy Vodolazhskiy ◽  
Yelena Frantsiyants ◽  
Svetlana Panina ◽  
E. Rastorguev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumor ◽  
Molecular Markers ◽  
Glioblastoma Multiforme ◽  
Somatic Mutations ◽  
Web Of Science ◽  
Molecular Subtypes ◽  
Regulation Of Gene Expression ◽  
Signal Pathways ◽  
Poorly Differentiated

Glioblastoma multiforme (GBM) is the most common and invasive poorly differentiated brain tumor with nearly 100 % rate of recurrence and unfavorable prognosis. The aim of the present review is to analyze recent studies and experimental results (Scopus, Web of Science, PubMed) concerning somatic mutations in glioblastoma, aberrant regulation of gene expression of signal pathways including EGFR, TGFß, etc. and markers for GBM progression. Particularly the molecular subtypes of glioblastoma and NGS results are considered in this review.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

Discovery of Novel 2-Amino-5-(Substituted)-1,3,4-Thiadiazole Derivatives: New Utilities for Colon Cancer Treatment

2018 ◽  
Vol 18 (5) ◽  
pp. 719-738 ◽  
Author(s):  
Vinit Raj ◽  
Amit Rai ◽  
Ashok K. Singh ◽  
Amit K. Keshari ◽  
Prakruti Trivedi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Metastasis ◽  
Molecular Targets ◽  
Cancer Cell Line ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Human Colon Cancer ◽  
Thiadiazole Derivatives ◽  
Ht 29

Background: Colon cancer is one of the most widespread disease, the mortality rate is high due to cancer metastasis and the development of drug resistance. In this regards, new chemotherapeutic agents with specific mechanisms of action and significant effect on patient’s survival are the new era for the colon cancer drug development. Objective: The main objective of present study was to design, synthesize of a novel series of 1,3,4-thiadiazole derivatives (VR1 to VR35) and screen them against HT-29 human colon cancer cell line. Method: Newly 1,3,4-thiadiazole scaffold were designed, synthesized and further, characterized by FTIR, NMR (1H and 13C), MS and elemental analyses. Before the synthesis, molecular dynamic simulation and ADME studies were performed to find out the most potent lead compounds. Later, SRB assay using HT-29 cells and ELISA assays were performed to explore activity and molecular targets of VR24 and VR27 and find out whether in silico data had a similar pattern in the molecular level. Results: The results of docking study revealed that both VR24 and VR27 had interaction energy >-5 kcal/mol with various assigned molecular targets and the ligand-protein complexes were found to be stable with IL-6. The computational analysis of molecules showed good ADMET profiling. Later, the in vitro anticancer study was conducted where VR24 and VR27 were found to be active against HT-29 cells (GI50<10 µM). Finally, ELISA assays revealed that both the compounds had higher inhibition properties to various biomarker of colon cancer like IL-6 and COX-2. Conclusion: Collectively, these result suggested that VR24 and VR27 inhibited the assigned molecular targets, imparting their ameliorative effects against colon cancer. Due to these encouraging results, we concluded that both VR24 and VR27 may be effective against colon cancer therapy in future.

scholarly journals High-resolution AP-SMALDI MSI as a tool for drug imaging in Schistosoma mansoni

2021 ◽  
Author(s):  
Annika S. Mokosch ◽  
Stefanie Gerbig ◽  
Christoph G. Grevelding ◽  
Simone Haeberlein ◽  
Bernhard Spengler
Keyword(s):  
Schistosoma Mansoni ◽  
Egg Production ◽  
Drug Repurposing ◽  
Cancer Drug ◽  
Ionization Mass ◽  
Parasitic Flatworm ◽  
Paired Female ◽  
First Time ◽  
Organ Tropism

AbstractSchistosoma mansoni is a parasitic flatworm causing schistosomiasis, an infectious disease affecting several hundred million people worldwide. Schistosomes live dioeciously, and upon pairing with the male, the female starts massive egg production, which causes pathology. Praziquantel (PZQ) is the only drug used, but it has an inherent risk of resistance development. Therefore, alternatives are needed. In the context of drug repurposing, the cancer drug imatinib was tested, showing high efficacy against S. mansoni in vitro. Besides the gonads, imatinib mainly affected the integrity of the intestine in males and females. In this study, we investigated the potential uptake and distribution of imatinib in adult schistosomes including its distribution kinetics. To this end, we applied for the first time atmospheric-pressure scanning microprobe matrix-assisted laser desorption/ionization mass spectrometry imaging (AP-SMALDI MSI) for drug imaging in paired S. mansoni. Our results indicate that imatinib was present in the esophagus and intestine of the male as early as 20 min after in vitro exposure, suggesting an oral uptake route. After one hour, the drug was also found inside the paired female. The detection of the main metabolite, N-desmethyl imatinib, indicated metabolization of the drug. Additionally, a marker signal for the female ovary was successfully applied to facilitate further conclusions regarding organ tropism of imatinib. Our results demonstrate that AP-SMALDI MSI is a useful method to study the uptake, tissue distribution, and metabolization of imatinib in S. mansoni. The results suggest using AP-SMALDI MSI also for investigating other antiparasitic compounds and their metabolites in schistosomes and other parasites. Graphical abstract

scholarly journals Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1411
Author(s):  
Don Carlo Ramos Batara ◽  
Moon-Chang Choi ◽  
Hyeon-Uk Shin ◽  
Hyunggee Kim ◽  
Sung-Hak Kim
Keyword(s):  
Brain Tumor ◽  
Glioblastoma Multiforme ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Primary Brain Tumor ◽  
Molecular Target ◽  
Therapeutic Strategies ◽  
Homeostatic Mechanism ◽  
Cellular Context ◽  
Cellular Components

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy’s pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.

scholarly journals Evaluation of Dimer of Epicatechin from an Endophytic Fungus Curvularia australiensis FC2AP on Acute Toxicity Levels, Anti-Inflammatory and Anti-Cervical Cancer Activity in Animal Models

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 654
Author(s):  
Vellingiri Manon Mani ◽  
Arockiam Jeyasundar Parimala Gnana Soundari ◽  
Balamuralikrishnan Balasubramanian ◽  
Sungkwon Park ◽  
Utthapon Issara ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Acute Toxicity ◽  
Endophytic Fungus ◽  
Lethal Dose ◽  
Chemotherapeutic Agents ◽  
Cancer Drug ◽  
Dependent Manner ◽  
Anti Cancer ◽  
Albino Mice ◽  
Anti Inflammatory

Cervical cancer, as the most frequent cancer in women globally and accounts almost 14% in India. It can be prevented or treated with vaccines, radiation, chemotherapy, and brachytherapy. The chemotherapeutic agents cause adverse post effects by the destruction of the neighboring normal cells or altering the properties of the cells. In order to reduce the severity of the side effects caused by the chemically synthesized therapeutic agents, the current research developed an anti-cancer agent dimer of epicatechin (DoE), a natural bioactive secondary metabolite (BSM) mediated from an endophytic fungus Curvularia australiensis FC2AP. The investigation has initiated with the evaluation of inhibiting the angiogenesis which is a main activity in metastasis, and it was assessed through Hen’s Egg Test on Chorio Allantoic Membrane (HET-CAM) test; the BSM inhibited the growth of blood vessels in the developing chick embryo. Further the DoE was evaluated for its acute toxicity levels in albino mice, whereas the survival dose was found to be 1250 mg/kg and the lethal dose was 1500 mg/kg body weight of albino mice; hematological, biochemical, and histopathological analyses were assessed. The anti-inflammatory responses of the DoE were evaluated in carrageenan induced Wistar rats and the reduction of inflammation occurred in a dose-dependent manner. By fixing the effective dose for anti-inflammation analysis, the DoE was taken for the anti-cervical cancer analysis in benzo (a) pyrene induced female Sprague-Dawley rats for 60 days trial. After the stipulated days, the rats were taken for hematological antioxidants, lipid peroxidation (LPO), member bound enzymes, cervical histopathological and carcinogenic markers analyses. The results specified that the DoE has the capability of reducing the tumor in an efficient way. This is the first report of flavonoid-DoE production from an endophytic fungus C. australiensis has the anticancer potentiality and it can be stated as anti-cancer drug.

scholarly journals DRUG REPOSITION OF NON-CANCER DRUGS FOR CANCER TREATMENTS VIA PHARMACOVIGILANCE APPROACH - REPURPOSING DRUGS IN ONCOLOGY

2019 ◽  
pp. 310-314 ◽  
Author(s):  
Mrugank Bhaskarkumar Parmar ◽  
Shital Panchal
Keyword(s):  
Statistical Analysis ◽  
Cancer Treatment ◽  
Drug Repositioning ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Cancer Drug ◽  
Cancer Drugs ◽  
Management Activity ◽  
Post Marketing Surveillance ◽  
Source Data

This study for drug repositioning has been performed for the drugs which are in the market since more than a decade and they are approved with their well-established efficacy and safety in human being. Objective of this study was to reposition the existing non-cancer drug therapy for cancer treatment, which is having well characterized pharmacologic profile with more efficacy and least toxicity as anti-neoplastic agent. We have retrieved the source data from FDA Adverse Event Reporting System (FAERS) for the last 13 years covering duration from 2004 to 2016 and analysed those using pharmacovigilance approach ‘a proposed future novel pharmaceutical tool for drug reposition’. Signal management activity was performed for statistical analysis. Result of statistical analysis derived that propranolol; metformin; pioglitazone; dabigatran and nitroglycerin are the existing non-cancer drugs which deserved for their direct / indirect reposition for cancer treatment and anti-neoplastic activity. Further studies retrieving the source data from other regulatory database (e.g. Eudravigilance of EMA and VigiFlow of WHO) and post-marketing surveillance study with the same objective may adjuvant our results for the reposition of existing drugs by pharmacovigilance approach.

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