scholarly journals Functional Stratification of Cancer Drugs through Integrated Network Similarity

2022 ◽  
Author(s):  
Nurcan Tuncbag ◽  
Seyma Unsal Beyge
Keyword(s):  
Cell Lines ◽  
Drug Targets ◽  
Hdac Inhibitors ◽  
Treatment Strategies ◽  
Network Models ◽  
Drug Combinations ◽  
Multiple Cancer ◽  
Integrated Network ◽  
Drug Molecules ◽  
The Difference

Abstract Heterogeneity across tumors is the main obstacle in developing treatment strategies. Drug molecules not only perturb their immediate protein targets but also modulate multiple signaling pathways. In this study, we explored the networks modulated by several drug molecules across multiple cancer cell lines by integrating the drug targets with transcriptomic and phosphoproteomic data. As a result, we obtained 236 reconstructed networks covering five cell lines and 70 drugs. A rigorous topological and pathway analysis showed that chemically and functionally different drugs may modulate overlapping networks. Additionally, we revealed a set of tumor-specific hidden pathways with the help of drug network models that are not detectable from the initial data. The difference in the target selectivity of the drugs leads to disjoint networks despite sharing the exact mechanism of action, e.g., HDAC inhibitors. We also used the reconstructed network models to study potential drug combinations based on the topological separation, found literature evidence for a set of drug pairs. Overall, the network-level exploration of the drug perturbations may potentially help optimize treatment strategies and suggest new drug combinations.

scholarly journals Landscape of Chimeric RNAs in Non-Cancerous Cells

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 466
Author(s):  
Chen Chen ◽  
Samuel Haddox ◽  
Yue Tang ◽  
Fujun Qin ◽  
Hui Li
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Drug Targets ◽  
Neoplastic Cell ◽  
Multiple Cancer ◽  
Chimeric Rnas ◽  
Healthy Donors ◽  
Cancer Types ◽  
Chimeric Rna ◽  
Cancerous Cells

Gene fusions and their products (RNA and protein) have been traditionally recognized as unique features of cancer cells and are used as ideal biomarkers and drug targets for multiple cancer types. However, recent studies have demonstrated that chimeric RNAs generated by intergenic alternative splicing can also be found in normal cells and tissues. In this study, we aim to identify chimeric RNAs in different non-neoplastic cell lines and investigate the landscape and expression of these novel candidate chimeric RNAs. To do so, we used HEK-293T, HUVEC, and LO2 cell lines as models, performed paired-end RNA sequencing, and conducted analyses for chimeric RNA profiles. Several filtering criteria were applied, and the landscape of chimeric RNAs was characterized at multiple levels and from various angles. Further, we experimentally validated 17 chimeric RNAs from different classifications. Finally, we examined a number of validated chimeric RNAs in different cancer and non-cancer cells, including blood from healthy donors, and demonstrated their ubiquitous expression pattern.

scholarly journals EMBR-11. SYNERGISTIC DRUG COMBINATIONS FOR THE TREATMENT OF MYC AMPLIFIED GROUP 3 MEDULLOBLASTOMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i7-i8
Author(s):  
Simon Zeuner ◽  
Johanna Vollmer ◽  
Heike Peterziel ◽  
Romain Sigaud ◽  
Sina Oppermann ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cell Lines ◽  
Hdac Inhibitors ◽  
Drug Combinations ◽  
Class I ◽  
Drug Screen ◽  
Synergistic Activity ◽  
Sensitivity Score ◽  
Group 3 ◽  
Synergistic Drug Combinations

Abstract Background Medulloblastoma (MB) is a highly aggressive brain tumour in children. Patients with Group 3 MB harbouring a MYC-amplification (subtype II) show a particularly poor outcome despite high-intensity multimodal therapy. We and others have previously shown that MYC amplified Group 3 MB cells are highly susceptible towards treatment with class I histone deacetylase (HDAC) inhibitors such as entinostat. However, in clinical trials HDACi as a monotherapy show only modest efficacy in solid tumours. We propose to increase the efficacy of class I HDACi by drug combinations. Methods To identify synergistic drug combinations (entinostat + X) for the treatment of MYC amplified MB we performed a drug screen with a library of n=75 clinically available compounds as single agents and in combination with entinostat in n=3 MYC amplified vs. n=1 MYC-non amplified cell lines. Synergistic behaviour of the six most promising drug combinations was validated by metabolic activity assays, cell count experiments and gene expression profiling. Synergy was assessed by the Loewe additivity model using a combination of ray design and checkerboard matrix. Results The drug screen revealed n=20/75 drugs that were particularly effective (drug sensitivity score ≥10) in combination with entinostat treatment in all three MYC amplified cell lines. Synergy assessment of the top n=6 drugs confirmed strong synergistic activity with entinostat for n=2 drugs (navitoclax, irinotecan). The BCL-2 family inhibitor navitoclax showed the most robust synergy with entinostat in subsequent validation experiments. Conclusion Several drugs either clinically available or currently in clinical trials, including the BCL-2/Xl/w inhibitor navitoclax, show promising effects in a combination therapy with entinostat for the treatment of MYC amplified Group 3 MB.

scholarly journals A Multiparametric Pharmacogenomic Strategy for Drug Repositioning predicts Therapeutic Efficacy for Glioblastoma Cell Lines

2021 ◽  
Author(s):  
Ashish H Shah ◽  
Robert Suter ◽  
Pavan Gudoor ◽  
Tara T Doucet-O’Hare ◽  
Vasileios Stathias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Lines ◽  
Drug Repositioning ◽  
Hdac Inhibitors ◽  
Drug Repurposing ◽  
The Cancer Genome Atlas ◽  
Treatment Modalities ◽  
Activity Data ◽  
Integrated Network ◽  
Disease Signature

Abstract Background Poor prognosis of glioblastoma patients and the extensive heterogeneity of glioblastoma at both the molecular and cellular level necessitates developing novel individualized treatment modalities via genomics-driven approaches. Methods This study leverages numerous pharmacogenomic and tissue databases to examine drug repositioning for glioblastoma. RNAseq of glioblastoma tumor samples from The Cancer Genome Atlas (TCGA, n=117) were compared to “normal” frontal lobe samples from Genotype-Tissue Expression Portal (GTEX, n=120) to find differentially expressed genes (DEGs). Using compound-gene expression data and drug activity data from the Library of Integrated Network-Based Cellular Signatures (LINCS, n=66,512 compounds) CCLE (71 glioma cell lines), and Chemical European Molecular Biology Laboratory (ChEMBL) platforms, we employed a summarized reversal gene expression metric (sRGES) to “reverse” the resultant disease signature for GBM and its subtypes. A multi-parametric strategy was employed to stratify compounds capable of blood brain barrier penetrance with a favorable pharmacokinetic profile (CNS-MPO). Results Significant correlations were identified between sRGES and drug efficacy in GBM cell lines in both ChEMBL(r=0.37,p<.001) and Cancer Therapeutic Response Portal (CTRP) databases (r=0.35, p<0.001). Our multiparametric algorithm identified two classes of drugs with highest sRGES and CNS-MPO: HDAC inhibitors (vorinostat and entinostat) and topoisomerase inhibitors suitable for drug repurposing. Conclusions Our studies suggest that reversal of glioblastoma disease signature correlates with drug potency for various GBM subtypes. This multiparametric approach may set the foundation for an early-phase personalized -omics clinical trial for glioblastoma by effectively identifying drugs that are capable of reversing the disease signature and have favorable pharmacokinetic and safety profiles.

Novel Conjugated Quinazolinone-Based Hydroxamic Acids: Design, Synthesis and Biological Evaluation

2020 ◽  
Vol 16 ◽  
Author(s):  
Tran Khac Vu ◽  
Nguyen Thi Thanh ◽  
Nguyen Van Minh ◽  
Nguyen Huong Linh ◽  
Nguyen Thi Phương Thao ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Cell Lines ◽  
Cancer Cell ◽  
Hdac Inhibitors ◽  
Cancer Cell Lines ◽  
Hydroxamic Acids ◽  
Biological Evaluation ◽  
Hdac Inhibition ◽  
Ic50 Value ◽  
Mcf 7

Background: Target-based approach to drug discovery currently attracts a great deal of interest from medicinal chemists in anticancer drug discovery and development. Histone deacetylase (HDAC) inhibitors represent an extensive class of targeted anti-cancer agents. Among the most explored structure moieties, hydroxybenzamides and hydroxypropenamides have been demonstrated to have potential HDAC inhibitory effects. Several compounds of these structural classes have been approved for clinical uses to treat different types of cancer, such as vorinostat and belinostat. Aims: This study aims at developing novel HDAC inhibitors bearing conjugated quinazolinone scaffolds with potential cytotoxicity against different cancer cell lines. Method: A series of novel N-hydroxyheptanamides incorporating conjugated 6-hydroxy-2 methylquinazolin-4(3H)- ones (15a-l) was designed, synthesized and evaluated for HDAC inhibitory potency as well as cytotoxicity against three human cancer cell lines, including HepG-2, MCF-7 and SKLu-1. Molecular simulations were finally performed to gain more insight into the structure-activity. relationships. Results: It was found that among novel conjugated quinazolinone-based hydroxamic acids synthesized, compounds 15a, 15c and 15f were the most potent, both in terms of HDAC inhibition and cytotoxicity. Especially, compound 15f displayed up to nearly 4-fold more potent than SAHA (vorinostat) in terms of cytotoxicity against MCF-7 cell line with IC50 value of 1.86 µM, and HDAC inhibition with IC50 value of 6.36 µM. Docking experiments on HDAC2 isozyme showed that these compounds bound to HDAC2 with binding affinities ranging from -10.08 to -14.93 kcal/mol compared to SAHA (-15.84 kcal/mol). It was also found in this research that most of the target compounds seemed to be more cytotoxic toward SKLu-1than MCF-7 and HepG-2. Conclusion: The resesrch results suggest that some hydroxamic acids could emerge for further evaluation and the results are well served as basics for further design of more potent HDAC inhibitors and antitumor agents.

scholarly journals Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

2021 ◽  
Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Targets ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Preclinical Study ◽  
Parp Cleavage ◽  
Rpmi 8226 ◽  
Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

scholarly journals Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 885
Author(s):  
Shin-Yi Chung ◽  
Yi-Ping Hung ◽  
Yi-Ru Pan ◽  
Yu-Chan Chang ◽  
Chiao-En Wu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Nuclear Translocation ◽  
Vital Role ◽  
First Line ◽  
Current Standard ◽  
Integrated Network ◽  
Jak2 Inhibitor ◽  
Therapeutic Drugs ◽  
Cholangiocarcinoma Cell ◽  
Malignant Behavior

Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and the cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the library of integrated network-based cellular signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy.

scholarly journals Identification of novel DNA hypermethylation of the adenylate kinase 5 promoter in colorectal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bokyung Ahn ◽  
Yang Seok Chae ◽  
Soo Kyung Lee ◽  
Moa Kim ◽  
Hyeon Soo Kim ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Cell Lines ◽  
Adenylate Kinase ◽  
Dna Methyltransferase ◽  
Colorectal Adenocarcinoma ◽  
Adenine Nucleotides ◽  
Inverse Correlation ◽  
Dna Hypermethylation ◽  
Normal Tissues ◽  
The Difference

AbstractAdenylate kinase 5 (AK5) belongs to the adenylate kinase family that catalyses reversible phosphate transfer between adenine nucleotides, and it is related to various energetic signalling mechanisms. However, the role of AK5 in colorectal cancer (CRC) has not been reported. In this study, AK5 was significantly hypermethylated in CRC compared to adjacent normal tissues (P < 0.0001) and normal tissues (P = 0.0015). Although the difference in mRNA expression was not statistically significant in all of them, the selected 49 cases of CRC tissues with AK5 hypermethylation with the cut off value of 40% showed a significant inverse correlation with mRNA expression (P = 0.0003). DNA methylation of AK5 promoter significantly decreased and AK5 expression recovered by 5-aza-2′-deoxycytidine, DNA methyltransferase inhibitor in CRC cell lines. In addition, AK5 promoter activity significantly decreased due to DNA methyltransferase, and it increased due to 5-aza. Moreover, AK5 regulated the phosphorylated AMPK and mTOR phosphorylation and inhibited the cell migration and cell invasion in CRC cell lines. Furthermore, low AK5 expression is associated with poor differentiation (P = 0.014). These results demonstrate that the AK5 promoter is frequently hypermethylated and induced methylation-mediated gene down-regulation. AK5 expression regulates AMPK/mTOR signalling and may be closely related to metastasis in colorectal adenocarcinoma.

scholarly journals Cytotoxic Profiling of Annotated and Diverse Chemical Libraries Using Quantitative High-Throughput Screening

2019 ◽  
Vol 25 (1) ◽  
pp. 9-20 ◽  
Author(s):  
Olivia W. Lee ◽  
Shelley Austin ◽  
Madison Gamma ◽  
Dorian M. Cheff ◽  
Tobie D. Lee ◽  
...  
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
High Throughput ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Large Scale ◽  
Early Stage ◽  
Cancer Cell Line ◽  
Hek 293 ◽  
Cytotoxic Compounds

Cell-based phenotypic screening is a commonly used approach to discover biological pathways, novel drug targets, chemical probes, and high-quality hit-to-lead molecules. Many hits identified from high-throughput screening campaigns are ruled out through a series of follow-up potency, selectivity/specificity, and cytotoxicity assays. Prioritization of molecules with little or no cytotoxicity for downstream evaluation can influence the future direction of projects, so cytotoxicity profiling of screening libraries at an early stage is essential for increasing the likelihood of candidate success. In this study, we assessed the cell-based cytotoxicity of nearly 10,000 compounds in the National Institutes of Health, National Center for Advancing Translational Sciences annotated libraries and more than 100,000 compounds in a diversity library against four normal cell lines (HEK 293, NIH 3T3, CRL-7250, and HaCat) and one cancer cell line (KB 3-1, a HeLa subline). This large-scale library profiling was analyzed for overall screening outcomes, hit rates, pan-activity, and selectivity. For the annotated library, we also examined the primary targets and mechanistic pathways regularly associated with cell death. To our knowledge, this is the first study to use high-throughput screening to profile a large screening collection (>100,000 compounds) for cytotoxicity in both normal and cancer cell lines. The results generated here constitute a valuable resource for the scientific community and provide insight into the extent of cytotoxic compounds in screening libraries, allowing for the identification and avoidance of compounds with cytotoxicity during high-throughput screening campaigns.

scholarly journals Histone deacetylase inhibitor panobinostat induces antitumor activity in epithelioid sarcoma and rhabdoid tumor by growth factor receptor modulation

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Anne Catherine Harttrampf ◽  
Maria Eugenia Marques da Costa ◽  
Aline Renoult ◽  
Estelle Daudigeos-Dubus ◽  
Birgit Geoerger
Keyword(s):  
Growth Factor ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Epithelioid Sarcoma ◽  
Hdac Inhibitors ◽  
Growth Factor Receptor ◽  
Rhabdoid Tumor ◽  
Tumor Growth Inhibition ◽  
Mesenchymal Transition ◽  
Receptor Modulation

Abstract Background Epithelioid sarcomas and rhabdoid tumors are rare, aggressive malignancies with poor prognosis. Both are characterized by INI1 alterations and deregulation of growth factor receptors albeit their interaction has not been elucidated. Methods In this study, we investigated the activity of a panel of epigenetic modulators and receptor tyrosine kinase inhibitors in vitro on respective cell lines as well as on primary patient-derived epithelioid sarcoma cells, and in vivo on xenografted mice. Focusing on histone deacetylase (HDAC) inhibitors, we studied the mechanism of action of this class of agents, its effect on growth factor receptor regulation, and changes in epithelial-to-mesenchymal transition by using cell- and RT-qPCR-based assays. Results Pan-HDAC inhibitor panobinostat exhibited potent anti-proliferative activity at low nanomolar concentrations in A204 rhabdoid tumor, and VAESBJ/GRU1 epithelioid sarcoma cell lines, strongly induced apoptosis, and resulted in significant tumor growth inhibition in VAESBJ xenografts. It differentially regulated EGFR, FGFR1 and FGFR2, leading to downregulation of EGFR in epithelioid sarcoma and to mesenchymal-to-epithelial transition whereas in rhabdoid tumor cells, EGFR was strongly upregulated and reinforced the mesenchymal phenotype. All three cell lines were rendered more susceptible towards combination with EGFF inhibitor erlotinib, further enhancing apoptosis. Conclusions HDAC inhibitors exhibit significant anticancer activity due to their multifaceted actions on cytotoxicity, differentiation and drug sensitization. Our data suggest that the tailored, tissue-specific combination of HDAC inhibitors with therapeutics which target cellular salvage mechanisms might increase their therapeutic relevance.

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