Anticancer Target Research Articles

Editorial: Discovery of small molecule lead compounds: a driving force to unravel new anti-cancer targets and mechanisms, Volume II

Editorial: Discovery of small molecule lead compounds: a driving force to unravel new anti-cancer targets and mechanisms, Volume II

Potential Antimicrobial and Cytotoxic Activity of Caralluma indica Seed Extract

Background: Plant-derived phytochemicals are crucial in fighting bacterial infections and in cancer therapy. Objective: This study investigates the phytochemical composition of the ethanolic extract obtained from Caralluma indica (C. indica) seeds and assesses its antimicrobial, anticancer, and antioxidant activities. Results: GC-MS analysis found 30 phytochemicals in C. indica seeds, including 5 bioactive compounds that have been shown to have antioxidant, antimicrobial, and cytotoxicity properties, through in silico evaluation. Phytochemical screening of C. indica identified and measured the phenolic compounds, providing insight into its bioactive potential and therapeutic properties. C. indica exhibited robust antioxidant capacity (DPPH, ABTS, nitric oxide, and H2O2 radical scavenging) alongside potent antimicrobial activity against oral pathogen and cytotoxicity activity on a human oral squamous carcinoma cell line (OECM-1) (EC50 of 169.35 µg/mL) and yeast cell Saccharomyces cerevisiae (215.82 µg/mL), with a selective index of 1.27. The subminimum % MBC/MFC of C. indica significantly reduced biofilm formation against oral pathogens (p < 0.05). Molecular docking studies showed a strong correlation (r = 0.862) between antifungal and anticancer targets, suggesting that the antimicrobial agents in C. indica contribute to cancer prevention mechanisms. Conclusions: These findings propose C. indica seeds as promising candidates for combating oral pathogens, inhibiting biofilm formation, and reducing the risk of oral cancer progression.

Strategic and Innovative Roles of lncRNAs Regulated by Naturally-derived Small Molecules in Cancer Therapy.

In the field of precision and personalized medicine, the next generation sequencing method has begun to take an active place as genome-wide screening applications in the diagnosis and treatment of diseases. Studies based on the determination of the therapeutic efficacy of personalized drug use in cancer treatment in the size of the transcriptome and its extension, lncRNA, have been increasing rapidly in recent years. Targeting and/or regulating noncoding RNAs (ncRNAs) consisting of long noncoding RNAs (lncRNAs) are promising strategies for cancer treatment. Within the scope of rapidly increasing studies in recent years, it has been shown that many natural agents obtained from biological organisms can potentially alter the expression of many lncRNAs associated with oncogenic functions. Natural agents include effective small molecules that provide anti-cancer effects and have been used as chemotherapy drugs or in combination with standard anti-cancer drugs used in routine treatment. In this review, it was aimed to provide detailed information about the potential of natural agents to regulate and/or target non-coding RNAs and their mechanisms of action to provide an approach for cancer therapy. The discovery of novel anti-cancer targets and subsequent development of effective drugs or combination strategies that are still needed for most cancers will be promising for cancer treatment.

The USP11/Nrf2 positive feedback loop promotes colorectal cancer progression by inhibiting mitochondrial apoptosis

AbstractAbnormal antioxidant capacity of cancer is closely related to tumor malignancy. Modulation of oxidative stress status is a novel anticancer therapeutic target. Nrf2 is a key regulator of various antioxidant enzymes, but the mechanism of its deubiquitination remains largely unclear. This study unveiled that Nrf2 received post-transcriptional regulation from a proteasome-associated deubiquitinating enzyme, USP11, in colorectal cancer (CRC). It was found that USP11 was overexpressed in CRC tissues acting as an oncogene by inhibiting mitochondrial apoptosis, and USP11 managed to maintain balance in the production and elimination of reactive oxygen species (ROS). Mechanistically, we identified a feedback loop between USP11 and Nrf2 maintaining the redox homeostasis. USP11 stabilized Nrf2 by deubiquitinating and protecting it from proteasome-mediated degradation. Interestingly, we also map that Nrf2 could bind to the antioxidant reaction element (ARE) in the USP11 promoter to promote its transcription. Hence, USP11/Nrf2 positive feedback loop inhibited mitochondrial apoptosis of CRC cells by activating Nrf2/ARE signaling pathway, thus promoting CRC progression.

The glycogene alterations and potential effects in esophageal squamous cell carcinoma

BackgroundAberrant glycosylation is one of the hallmarks of cancer. The profile of glycoprotein expression caused by abnormal glycosylation has been revealed, while abnormal glycogenes that may disturb the structure of glycans have not yet been identified in esophageal squamous cell carcinoma (ESCC).MethodsGenomic alterations driven by differentially expressed glycogenes in ESCC were compared with matched normal tissues by multi-omics analysis. Immunohistochemistry, MTT, colony formation, transwell assays, subcutaneous tumor formation experiments and tail vein injection were used to study the expression and the effect on the proliferation and metastasis of the differentially expressed glycogenes POFUT1 and RPN1 in ESCC. In the alkyne fucose labeling experiment, AAL lectin affinity chromatography and immunoprecipitation were used to explore the mechanism of POFUT1 in ESCC.ResultsThe expression of the POFUT1 and RPN1 glycogenes were upregulated, as determined by genomic copy number gain and proteomics analysis. The overexpression of POFUT1 or RPN1 was associated with poor prognosis in ESCC patients and affected the proliferation and metastasis of ESCC in vivo and in vitro. The overexpression of POFUT1 increased the overall fucosylation level and activated the Notch signaling pathway, which partially mediated POFUT1 induced pro-migration in ESCC. The regulation of malignant progression of ESCC by RPN1 may be related to the TNF signaling pathway, p53 signaling pathway, etc.ConclusionsOur study fills a gap in the study of abnormal glycogenes and highlights the potential role of the POFUT1/Notch axis in ESCC. Moreover, our study identifies POFUT1 and RPN1 as promising anticancer targets in ESCC.

Integration of transcriptional and epigenetic regulation of TFEB reveals its dual functional roles in Pan-cancer.

Transcription factor EB (TFEB) mainly regulates the autophagy-lysosomal pathway, associated with many diseases, including cancer. However, the role of TFEB in pan-cancer has not been investigated systematically. In this study, we comprehensively analyzed TFEB targets under three stresses in Hela cells by cross-validation of RNA-seq and ChIP-seq. 1712 novel TFEB targets have not been reported in the Gene Set Enrichment Analysis and ChIP Enrichment Analysis databases. We further investigated their distributions and roles among the pan-cancer co-expression networks across 32 cancers constructed by multiscale embedded gene co-expression network analysis (MEGENA) based on the Cancer Genome Atlas (TCGA) cohort. Specifically, TFEB might serve as a hidden player with multifaceted functions in regulating pan-cancer risk factors, e.g. CXCL2, PKMYT1and BUB1, associated with cell cycle and immunosuppression. TFEB might also regulate protective factors, e.g. CD79A, related to immune promotion in the tumor microenvironment. We further developed a Shiny app website to present the comprehensive regulatory targets of TFEB under various stimuli, intending to support further research on TFEB functions. Summarily, we provided references for the TFEB downstream targets responding to three stresses and the dual roles of TFEB and its targets in pan-cancer, which are promising anticancer targets that warrant further exploration.

CD70: An Emerging Anticancer Target in Renal Cell Carcinoma and Beyond.

CD70 is an emerging target for anticancer therapies. It is an ideal antigen target given its limited expression in normal physiologic tissues and propensity to be aberrantly expressed in a variety of malignancies, thus limiting off-target toxicities. It is also heavily involved in immune homeostasis, and disruption of this pathway can help overcome tumor-related immune cell exhaustion. Recent phase I/II trials using cellular therapies targeting CD70, such as chimeric antigen receptor-T cells, have shown promising effectiveness and safety in treating relapsed or refractory renal cell carcinoma. Noncellular therapies targeting CD70, such as antibody-drug conjugates, monoclonal antibodies, radionuclides, and cytokines, are currently under investigation, with early data showing encouraging results as well. Efforts are already underway to further improve and optimize CD70-based therapies.

Riddelline from Tamarix articulate as a potential anti-bacterial lead compound for novel antibiotics discovery: A comprehensive computational and toxicological studies.

Tamarix articulate from the Tamaricaece family is a halophytic plant. This plant is commonly called Athal or Tamarix in different Arabic and Asian countries. Due to the high load of polyphenolic phytochemicals, the plant has been used as a therapeutic option against several diseases for decades. The plant is an anti-inflammatory, anti-bacterial, anti-viral, anti-cancer, anti-oxidant, and anti-inflammatory. In this work, the 222 phytochemical compounds of T. articulate from our previous study are used in different bioinformatic and biophysics techniques to explore their biological potency against different anti-bacterial, anti-cancer and anti-viral targets. By doing so, it was found that Riddelline ranked as the best binding molecule of biological macromolecules selected herein in particular the bacterial targets. The binding energy value of the compound for the KdsA enzyme was -14.64 kcal/mol, KdsB (-13.09 kcal/mol), MurC (-13.67 kcal/mol), MurD (-13.54 kcal/mol), MurF (-14.20 kcal/mol), Polo-like kinase 1 (Plk1) (-12.34 kcal/mol), Bcl-2 protein (-13.39 kcal/mol), SARS-CoV-2 main protease enzyme (-12.67 kcal/mol), and Human T cell leukemia virus protease (-13.67 kcal/mol). The mean Rg value of KdsA-Riddelline complex and KdsA-FPE complex is 32.67 Å, and average RMSD of KdsA-Riddelline complex and KdsA-FPE complex is 2.31 Å, respectively. The binding energy complexes was found to be dominated by van der Waals (-71.98 kcal/mol for KdsA-Riddelline complex and -65.09 kcal/mol for KdsA-FPE complex). The lead compound was also unveiled to show favorable druglike properties and pharmacokinetics. Together, the data suggest the good anti-bacterial activities of the T. articulate phytochemicals and thus can be subjected to experimental in vitro and in vivo investigations.

Cinnamaldehyde as a Potential Cathepsin-B Inhibitor: A Comparative Investigation with some Commercial Anticancer Drugs.

Cancer is a leading cause of death worldwide, surpassed only by heart disease. Despite improved diagnosis and treatment, cancer cells still evade normal physiological processes such as apoptosis, metabolism, angiogenesis, cell cycle, and epigenetics. To mitigate the numerous side effects linked to chemotherapy, leveraging natural products emerged as a promising alternative, either alone or in tandem with traditional agents. Cinnamaldehyde, an active ingredient of Cinnamomum cassia's stem bark has emerged as a molecule of research with diverse pharmacological properties. In the present study, we report an in silico potential of cinnamaldehyde (CM) potential as an anticancer agent across thirteen anti-cancer targets in comparison with chlorambucil (CB), docetaxel (DOC), melphalan (MP). Computational tools such as DFT, CHEM3D, molinspiration, vNNADMET, SWISS ADME, admetSAR, galaxyrefine, iGEMDOCK, and DS-Visualizer were employed. Additionally, anti-cathepsin B activity was assessed for cinnamaldehyde and the commercial drugs CB, DOC, MP and the results showed 52.76, 62.41, 72.48 and 65.52 % inhibition respectively which is comparable. The results supported molecular docking using iGEMDOCK. Both in silico and experimental findings substantiate cinnamaldehyde as a promising drug for cancer treatment including metastasis and invasion where cathepsin B involvement is indicated.

Advancing Topoisomerase Research Using DNA Nanotechnology.

In this Perspective, the use of DNA nanotechnology is explored as a powerful tool for studying a family of enzymes known as topoisomerases. These enzymes regulate DNA topology within a living cell and play a major role in the pharmaceutical field, serving as anti-cancer and anti-bacterial targets. This Perspective will provide a short historical overview of the methods employed in studying these enzymes and emphasizing recent advancements in assays using DNA nanotechnology. These innovations have substantially improved accuracy and expanded the understanding of enzyme activity. This perspective will showcase the versatile utility of DNA nanotechnology in advancing scientific knowledge and its application in exploring new drug candidates, particularly in the study of topoisomerase enzymes.

TOWARDS THE DESIGN OF LIGANDS OF THE INTERNAL POCKET TEADS C-TERMINAL DOMAIN

The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration.

Optimizing the screening process for inhibitory aptamers specific to folate receptor alpha on an integrated, shear force-controlling microfluidic system

Folate receptor alpha (FRα) has been regarded as a promising target for ovarian cancer (OvCa) therapy. This work focused on improving the identification of inhibitory aptamers that specifically target and block FRα. A new integrated microfluidic system (IMS) was designed to automate the entire systematic evolution of ligands by exponential enrichment (SELEX), precisely controlling the washing shear force from 62.7 nN to 451.7 nN that gradually washed away low-affinity aptamers, allowing high-affinity, high-specificity, single-stranded DNA aptamers to be screened within 15 hours, which is significantly shorter than conventional process (weeks to months) while consuming 50% less samples and reagents. Furthermore, screened aptamers significantly inhibited OvCa progression, achieving 20% higher wound recovery in wound-healing tests when compared with an anti-cancer drug targeting FRα. In summary, precisely controlled shear force by IMS could optimize aptamers screening with high affinity/specificity towards FRα, which inhibited OvCa cell growth, suggesting their applicability as promising candidates for onco-therapy.

Mechanisms of Action of HSP110 and Its Cognate Family Members in Carcinogenesis.

Tumors, as chronic malignant diseases that account for about 20% of all deaths worldwide, are the number one threat to human health. Until now there is no reliable treatment for most types of tumors. Tumorigenesis and cellular carcinogenesis remain difficult challenges due to their complex etiology and unknown mechanisms. As stress process regulating molecules and protein folding promoters, heat shock proteins (HSPs) play an important role in cancer development. Most studies have shown that HSPs are one of the major anticancer drug targets. HSPs are not only modulators of the cellular stress response, but are also closely associated with tumor initiation, progression, and drug resistance, so understanding the mechanism of the HSP family involved in cellular carcinogenesis is an important part of understanding tumorigenesis and enabling anticancer drug development. In this review, we discuss the functions and mechanisms of key members of the HSP family (HSP70, HSP90, and HSP110) in participating in the process of tumorigenesis and cell carcinogenesis, and look forward to the prospect of key members of the HSP family in targeted cancer therapy.

Expression Profiling Identified TRPM7 and HER2 as Potential Targets for the Combined Treatment of Cancer Cells.

TRPM7 is a divalent cation-permeable channel that is highly active in cancer cells. The pharmacological inhibitors of TRPM7 have been shown to suppress the proliferation of tumor cells, highlighting TRPM7 as a new anticancer drug target. However, the potential benefit of combining TRPM7 inhibitors with conventional anticancer therapies remains unexplored. Here, we used genome-wide transcriptome profiling of human leukemia HAP1 cells to examine cellular responses caused by the application of NS8593, the potent inhibitor of the TRPM7 channel, in comparison with two independent knockout mutations in the TRPM7 gene introduced by the CRISPR/Cas9 approach. This analysis revealed that TRPM7 regulates the expression levels of several transcripts, including HER2 (ERBB2). Consequently, we examined the TRPM7/HER2 axis in several non-hematopoietic cells to show that TRPM7 affects the expression of HER2 protein in a Zn2+-dependent fashion. Moreover, we found that co-administration of pharmacological inhibitors of HER2 and TRPM7 elicited a synergistic antiproliferative effect on HER2-overexpressing SKBR3 cells but not on HER2-deficient MDA-MB-231 breast cancer cells. Hence, our study proposes a new combinatorial strategy for treating HER2-positive breast cancer cells.

Phytochemical composition, in vitro cytotoxicity, and in silico docking properties of Tamarix tetragyna L.

Tamarix tetragyna is a plant grows in Mediterranean area and some Arab countries. It possesses numerous medicinal values. Purpose of our study is to explore biological activity of tamarix tetragyna extracts of both leaves and stem with investigating their phytochemical composition. The investigated extracts’ phyto-constituent composition was determined using gas chromatographic-mass spectrometric method. In addition, in vitro cytoxicity activity versus cancer cell lines such MCF-7, HepG-2, HCT-116, and A-549 was examined by MTT assay method, together with exploring its apoptosis effect by flow cytometry and western blot analysis techniques. Moreover, some phytochemical compounds were identified, and in-silico evaluated against anticancer molecular targets. Plant extracts showed good cytotoxic activity against both A-549 and HCT-116 cancer cell lines. With an IC50 value of 23.90 µg/ml that led to apoptosis and G2/M-phase arrest in A-549 cells, cytotoxicity data demonstrate leaves’ extract effectiveness against these cells. Upon GC-MS analysis, it revealed presence of some bioactive components such as Stigmast-5-en-3-ol and 2-methoxy-4-vinyl phenol, which are known for their cytotoxic activity. Our findings suggest that methanolic extracts of Tamarix tetragyna parts may have potential therapeutic uses as anticancer against A-549 cells, which opens up further avenues for investigation into its industrial applications.

Discovery of Jaspamycin from marine-derived natural product based on MTA3 to inhibit hepatocellular carcinoma progression

Studies have underscored the pivotal role of metastasis-associated protein 3 (MTA3) as a cancer regulator, yet its potential as a drug target across cancers necessitates comprehensive evaluation. In this study, we analyzed MTA3 expression profiles to ascertain its diagnostic and prognostic value in pan-cancers, probing associations with genetic variations and immunological characteristics. Notably, liver hepatocellular carcinoma (LIHC) exhibited the most significant correlation with MTA3. By transfection of siRNA, interference of MTA3 affected HepG2 and Hepa1-6 cell viability and migration. Through drug screening and drug-likeness evaluation among marine-derived natural products, Jaspamycin was identified as a potential hepatocellular carcinoma treatment by targeting MTA3. By applying in vitro and in vivo experiment, the inhibitory effects of Jaspamycin on hepatocellular carcinoma viability, migration, and tumor progression were observed. To assess the potential of MTA3 as an anticancer drug target, MTA3 overexpression plasmid was transfected together with Jaspamycin treatment, and observed that MTA3 upregulation counteracted the inhibitory effects of Jaspamycin on hepatocarcinoma cell proliferation and migration, underscoring the efficacy of MTA3 as a drug target in hepatocellular carcinoma drug screening. This study highlights the clinical significance of MTA3 in pan-cancer, particularly in hepatocellular carcinoma. Additionally, it identifies Jaspamycin, a marine-derived compound with promising pharmacological properties, as an effective inhibitor of MTA3 activity, suggesting its potential for hepatocellular carcinoma treatment.

Benchmarking machine learning methods for synthetic lethality prediction in cancer

Synthetic lethality (SL) is a gold mine of anticancer drug targets, exposing cancer-specific dependencies of cellular survival. To complement resource-intensive experimental screening, many machine learning methods for SL prediction have emerged recently. However, a comprehensive benchmarking is lacking. This study systematically benchmarks 12 recent machine learning methods for SL prediction, assessing their performance across diverse data splitting scenarios, negative sample ratios, and negative sampling techniques, on both classification and ranking tasks. We observe that all the methods can perform significantly better by improving data quality, e.g., excluding computationally derived SLs from training and sampling negative labels based on gene expression. Among the methods, SLMGAE performs the best. Furthermore, the methods have limitations in realistic scenarios such as cold-start independent tests and context-specific SLs. These results, together with source code and datasets made freely available, provide guidance for selecting suitable methods and developing more powerful techniques for SL virtual screening.

Crystallization and crystallographic studies of human serine protease inhibitor (serpin) B9.

Serine protease inhibitor B9 (serpin B9, also known as protease inhibitor 9 or PI9) plays a critical role in regulating the immune response by specifically inhibiting granzyme B, a serine protease found in cytotoxic T lymphocytes and natural killer cells. Despite its potential as an anticancer drug target, the structural details of serpin B9 have remained elusive until now. In this study, a cleaved form of recombinant human serpin B9 was successfully prepared and crystallized. The crystals belonged to space group P212121, with unit-cell parameters a = 68.51, b = 82.32, c = 101.17 Å, and an X-ray diffraction data set was collected at 1.9 Å resolution. The structure shows that serpin B9 adopts a relaxed conformation, with its cleaved reactive-centre loop inserted into the central β-sheet. Unlike other serpins, serpin B9 shows significant structural deviations around helix D, with a larger surface cavity, which could serve as a promising target for small-molecule inhibitors.

Application of Machine Learning Methods in Predicting Lysine-specific Histone Demethylase 1 (LSD1) Inhibitors

Background: Lysine-specific histone demethylase 1 (LSD1) is a well-known anti-cancer target for drug discovery. Novel reversible inhibitors of LSD1 are desirable to be developed. Objective: This study aimed to build reliable predictive models to evaluate the antineoplastic efficacy of compounds and reveal the structural foundation underlying the inhibitory activity of LSD1. Methods: Multiple artificial intelligence algorithms were utilized in the development of quantitative structure-activity relationship (QSAR) models. A dataset comprising 915 compounds with welldefined IC50 values against LSD1 was assembled for analysis. The structures of these compounds were described by different descriptor packages. Principal component analysis (PCA) was performed to explore the chemical space distribution of each dataset. Y-randomization test and applicability domain (AD) analysis were deployed to validate the reliability of models. Results: For regression models, a consensus model was constructed by integrating the predictions of four top-performing individual models (SVM_ECFP4, RFR_PyDescriptor, RFR_RDKIT, and TRANSNNI), resulting in enhanced predictive performance as compared to the individual models. The consensus model achieved a determination coefficient (r2, for the test set) value of 0.82. For classification models, the consensus model was derived from the amalgamation of three individual models (ASNN_RDKIT, ASNN_ECFP4, and RFR_ECFP4), and the overall prediction accuracy of the model was 0.96 for external validation. Conclusion: The reliable models could be used to identify highly active LSD1 inhibitors for the purpose of efficient virtual screening. In addition, the important molecular properties and structural fragments derived from this work can provide guidance for the structural optimization of novel LSD1 inhibitors.

Molecular docking and dynamics simulation of farnesol as a potential anticancer agent targeting mTOR pathway.

Farnesol is a natural acyclic sesquiterpene alcohol, found in various essential oils such as, lemon grass, citronella, tuberose, neroli, and musk. It has a molecular mass of 222.372g/mol and chemical formula of C₁₅H₂₆O. The main objective of this study was to assess the effect of farnesol on mTOR and its two downstream effectors, p70S6K and eIF4E, which are implicated in the development of cancer, via molecular dynamic simulation, and docking analysis in an in silico study. A multilayer, primarily computer-based analysis was conducted to assess farnesol's anticancer potential, with a focus on primary cancer targets. From the calculations performed, farnesol showed a binding affinity of - 9.66kcal/mol, followed by binding affinity of - 7.4kcal/mol and - 7.8kcal/mol for mTOR, p70S6K and eIF4E respectively. Rapamycin showed the binding affinity of - 10.45kcal/mol for mTOR, for p70S6K and eIF4E the calculated binding affinity was - 10.65kcal/mol and 8.16kcal/mol respectively. The binding affinity of farnesol was comparable to the standard drug rapamycin indicating its potential as an mTOR inhibitor. Molecular dynamics simulations suggest that the ligands (farnesol and rapamycin) were well trapped within the active site of the protein over a time gap of 50 ns. It is clear that farnesol showed relatively stable MD simulation results, with minor fluctuations and maintains a consistent binding orientation, suggesting a strong and stable interaction with the target proteins when compared to simulation data of standard drug. This study explores the potential of farnesol as an anticancer agent through an in-silico approach, focusing on its interaction with mTOR and its downstream effectors. Inhibition of mTOR signaling pathway may be responsible for the anticancer effect of farnesol. As this pathway plays a crucial role in cell proliferation and survival, making it a significant target in cancer research.