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Heliyon Apr 2023Phenotypic plasticity (PP) is a major promoter of tumor metastasis and drug resistance. Nevertheless, the molecular features and clinical significance of phenotypic...
BACKGROUND
Phenotypic plasticity (PP) is a major promoter of tumor metastasis and drug resistance. Nevertheless, the molecular features and clinical significance of phenotypic plasticity in lung squamous cell carcinomas (LSCC) remained largely unexplored.
METHODS
Phenotypic plasticity-related genes (PPRG) and clinical information of LSCC were downloaded from the cancer genome atlas (TCGA). The expression profiles of PPRG were compared between patients with and without lymph node metastasis. The prognostic signature was constructed, and survival analysis was performed based on phenotypic plasticity. Immunotherapy responses, chemotherapeutic drugs and targeted drug responses were investigated. In addition, the results were verified in an external cohort.
RESULTS
Patients with and without lymph node metastasis exhibited significantly different genomic characteristics of phenotypic plasticity. Enrichment analysis showed that PP was strongly associated with cell responses and cell contraction. Survival analysis demonstrated that PPRG could serve as independent prognostic factor for overall survival. The phenotypic plasticity-related signature successfully divided patients into high- and low-PP score groups. Patients with low-PP scores were more sensitive to PD-L1, Cisplatin, Gefitinib, Obatoclax. Mesylate, Paclitaxel, Sorafenib and Vinorelbine (all p < 0.05). While, patients with low-PP scores were more sensitive to Axitinib and Camptothecin (all p < 0.05). Consistent with the results from TCGA, the external cohort validated the above findings.
CONCLUSIONS
Our study revealed that phenotypic plasticity may be involved in the lymph node metastasis in LSCC through regulating cell responses and cell contraction. Evaluation of phenotypic plasticity will assist clinicians in making treatment strategies.
PubMed: 37025908
DOI: 10.1016/j.heliyon.2023.e14614 -
Molecules (Basel, Switzerland) Feb 2023In the present study, the binding affinity of 52 bioactive secondary metabolites from towards the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein (PDB: 2W3L) structure...
Computational Studies of Bioactive Secondary Metabolites from against Anti-Apoptotic B-Cell Lymphoma-2 (Bcl-2) Protein Associated with Cancer Cell Survival and Resistance.
In the present study, the binding affinity of 52 bioactive secondary metabolites from towards the anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein (PDB: 2W3L) structure was identified by using in silico molecular docking and molecular dynamics simulation. The molecular docking results demonstrated that the binding energies of docked compounds with Bcl-2 protein ranged from -5.3 kcal/mol to -10.1 kcal/mol. However, the lowest binding energy (-10.1 kcal/mol) was offered by Friedelin against Bcl-2 protein when compared to other metabolites and the standard drug Obatoclax (-8.4 kcal/mol). The molecular dynamics simulations revealed that the Friedelin-Bcl-2 protein complex was found to be stable throughout the simulation period of 100 ns. Overall, the predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) properties of Friedelin are relatively better than Obatoclax, with the most noticeable differences in many parameters where Friedelin has no AMES toxicity, hepatotoxicity, and skin sensitization. The ADMET profiling of selected compounds supported their in silico drug-likeness properties. Based on the computational analyses, the present study concluded that Friedelin of was found to be the potential inhibitor of the Bcl-2 protein, which merits attention for further in vitro and in vivo studies before clinical trials.
Topics: Humans; Apoptosis Regulatory Proteins; Cell Survival; Molecular Docking Simulation; Molecular Dynamics Simulation; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Wedelia; Phytochemicals
PubMed: 36838574
DOI: 10.3390/molecules28041588 -
Translational Cancer Research Jan 2023Hepatocellular carcinoma (HCC) is a common malignancy. Ferroptosis and cuproptosis promote HCC spread and proliferation. While fewer studies have combined ferroptosis...
Ferroptosis and cuproptosis prognostic signature for prediction of prognosis, immunotherapy and drug sensitivity in hepatocellular carcinoma: development and validation based on TCGA and ICGC databases.
BACKGROUND
Hepatocellular carcinoma (HCC) is a common malignancy. Ferroptosis and cuproptosis promote HCC spread and proliferation. While fewer studies have combined ferroptosis and cuproptosis to construct prognostic signature of HCC. This work attempts to establish a novel scoring system for predicting HCC prognosis, immunotherapy, and medication sensitivity based on ferroptosis-related genes (FRGs) and cuproptosis-related genes (CRGs).
METHODS
FerrDb and previous literature were used to identify FRGs. CRGs came from original research. The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases included the HCC transcriptional profile and clinical information [survival time, survival status, age, gender, Tumor Node Metastasis (TNM) stage, etc.]. Correlation, Cox, and least absolute shrinkage and selection operator (LASSO) regression analyses were used to narrow down prognostic genes and develop an HCC risk model. Using "caret", R separated TCGA-HCC samples into a training risk set and an internal test risk set. As external validation, we used ICGC samples. We employed Kaplan-Meier analysis and receiver operating characteristic (ROC) curve to evaluate the model's clinical efficacy. CIBERSORT and TIMER measured immunocytic infiltration in high- and low-risk populations.
RESULTS
[hazard ratio (HR) =1.477, P<0.001], (HR =1.373, P=0.001), (HR =1.650, P=0.004), (HR =1.576, P=0.002), (HR =1.728, P=0.008), (HR =1.826, P=0.002), (HR =1.596, P=0.005), (HR =1.290, P=0.002), and (HR =1.306, P<0.001) were distinguished to build predictive model. In both the model cohort (P<0.001) and the validation cohort (P<0.05), low-risk patients had superior overall survival (OS). The areas under the curve (AUCs) of the ROC curves in the training cohort (1-, 3-, and 5-year AUCs: 0.751, 0.727, and 0.743), internal validation cohort (1-, 3-, and 5-year AUCs: 0.826, 0.624, and 0.589), and ICGC cohort (1-, 3-, and 5-year AUCs: 0.699, 0.702, and 0.568) were calculated. Infiltration of immune cells and immunological checkpoints were also connected with our signature. Treatments with BI.2536, Epothilone.B, Gemcitabine, Mitomycin.C, Obatoclax. Mesylate, and Sunitinib may profit high-risk patients.
CONCLUSIONS
We analyzed FRGs and CRGs profiles in HCC and established a unique risk model for treatment and prognosis. Our data highlight FRGs and CRGs in clinical practice and suggest ferroptosis and cuproptosis may be therapeutic targets for HCC patients. To validate the model's clinical efficacy, more HCC cases and prospective clinical assessments are needed.
PubMed: 36760376
DOI: 10.21037/tcr-22-2203 -
Pharmaceutics Dec 2022Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a...
Metastasis is the primary cause of death in cancer patients. Many current chemotherapeutic agents only show cytotoxic, but not antimetastatic properties. This leads to a reduction in tumor size, but allows cancer cells to disseminate, which ultimately causes patient death. Therefore, novel anticancer compounds with both effects need to be developed. In this work, we analyze the antimetastatic properties of prodigiosin and obatoclax (GX15-070), anticancer drugs of the Prodiginines (PGs) family. We studied PGs' effects on cellular adhesion and morphology in the human primary and metastatic melanoma cell lines, SK-MEL-28 and SK-MEL-5, and in the murine melanoma cell line, B16F10A. Cell adhesion sharply decreased in the treated cells, and this was accompanied by a reduction in filopodia protrusions and a significant decrease in the number of focal-adhesion structures. Moreover, cell migration was assessed through the wound-healing assay and cell motility was severely inhibited after 24 h of treatment. To elucidate the molecular mechanisms involved, changes in metastasis-related genes were analyzed through a gene-expression array. Key genes related to cellular invasion, migration and chemoresistance were significantly down-regulated. Finally, an in vivo model of melanoma-induced lung metastasis was established and significant differences in lung tumors were observed in the obatoclax-treated mice. Altogether, these results describe, in depth, PGs' cellular antimetastatic effects and identify in vivo antimetastatic properties of Obatoclax.
PubMed: 36678726
DOI: 10.3390/pharmaceutics15010097 -
Oncotarget Jan 2023Overexpression of the dihydrolipoamide S-succinyltransferase () is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and...
Overexpression of the dihydrolipoamide S-succinyltransferase () is associated with poor outcome in neuroblastoma patients and triple-negative breast cancer (TNBC) and specifically with the oxidative phosphorylation (OXPHOS) pathway. Inhibitors of OXPHOS were previously suggested as a potential therapeutic strategy for a subset of patients with high-risk neuroblastoma. Here, we tested if cell lines with amplifications or high mRNA levels were associated with sensitivity to 250 drugs from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset by comparing them to cell lines without these changes. -altered cell lines were more sensitive to 7 approved drugs, among these obatoclax mesylate, a BCL2 inhibitor that reduces OXPHOS in human leukemia stem cells. Moreover, several protein kinase inhibitors were identified to be efficient in cell lines with amplifications or high mRNA levels, suggesting a vulnerability of -altered cell lines for drugs targeting the ERK/MAPK pathway. Furthermore, increased expression in cell lines with driver mutations in supported this relationship. We therefore conclude that, in addition to OXPHOS, protein kinases could be potential targets of therapy in the presence of amplifications or high mRNA levels. The new drug candidates proposed here could serve in experimental testing on drug efficacy in knock-in cell lines and -activated tumors.
Topics: Humans; RNA, Messenger; Cell Line; Neuroblastoma; Cell Line, Tumor
PubMed: 36634214
DOI: 10.18632/oncotarget.28342 -
International Journal of Molecular... Nov 2022Bladder cancer is the 10th most common cancer worldwide. Due to the lack of understanding of the oncogenic mechanisms between muscle-invasive bladder cancer (MIBC) and...
Systems Drug Design for Muscle Invasive Bladder Cancer and Advanced Bladder Cancer by Genome-Wide Microarray Data and Deep Learning Method with Drug Design Specifications.
Bladder cancer is the 10th most common cancer worldwide. Due to the lack of understanding of the oncogenic mechanisms between muscle-invasive bladder cancer (MIBC) and advanced bladder cancer (ABC) and the limitations of current treatments, novel therapeutic approaches are urgently needed. In this study, we utilized the systems biology method via genome-wide microarray data to explore the oncogenic mechanisms of MIBC and ABC to identify their respective drug targets for systems drug discovery. First, we constructed the candidate genome-wide genetic and epigenetic networks (GWGEN) through big data mining. Second, we applied the system identification and system order detection method to delete false positives in candidate GWGENs to obtain the real GWGENs of MIBC and ABC from their genome-wide microarray data. Third, we extracted the core GWGENs from the real GWGENs by selecting the significant proteins, genes and epigenetics via the principal network projection (PNP) method. Finally, we obtained the core signaling pathways from the corresponding core GWGEN through the annotations of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway to investigate the carcinogenic mechanisms of MIBC and ABC. Based on the carcinogenic mechanisms, we selected the significant drug targets NFKB1, LEF1 and MYC for MIBC, and LEF1, MYC, NOTCH1 and FOXO1 for ABC. To design molecular drug combinations for MIBC and ABC, we employed a deep neural network (DNN)-based drug-target interaction (DTI) model with drug specifications. The DNN-based DTI model was trained by drug-target interaction databases to predict the candidate drugs for MIBC and ABC, respectively. Subsequently, the drug design specifications based on regulation ability, sensitivity and toxicity were employed as filter criteria for screening the potential drug combinations of Embelin and Obatoclax for MIBC, and Obatoclax, Entinostat and Imiquimod for ABC from their candidate drugs. In conclusion, we not only investigated the oncogenic mechanisms of MIBC and ABC, but also provided promising therapeutic options for MIBC and ABC, respectively.
Topics: Humans; Urinary Bladder Neoplasms; Deep Learning; Microarray Analysis; Drug Design; Muscles
PubMed: 36430344
DOI: 10.3390/ijms232213869 -
IScience Sep 2022Pharmacologically active compounds with known biological targets were evaluated for inhibition of SARS-CoV-2 infection in cell and tissue models to help identify potent...
Pharmacologically active compounds with known biological targets were evaluated for inhibition of SARS-CoV-2 infection in cell and tissue models to help identify potent classes of active small molecules and to better understand host-virus interactions. We evaluated 6,710 clinical and preclinical compounds targeting 2,183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target, and cell interactome produced cellular networks important for infection. This analysis revealed 389 small molecules with micromolar to low nanomolar activities, representing >12 scaffold classes and 813 host targets. Representatives were evaluated for mechanism of action in stable and primary human cell models with SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of host factor dependencies and treatments for viral diseases.
PubMed: 35992305
DOI: 10.1016/j.isci.2022.104925 -
Chemical Science Jul 2022Small molecules and antibodies are normally considered separately in drug discovery, except in the case of covalent conjugates. We unexpectedly discovered several small...
Small molecules and antibodies are normally considered separately in drug discovery, except in the case of covalent conjugates. We unexpectedly discovered several small molecules that could inhibit or enhance antibody-epitope interactions which opens new possibilities in drug discovery and therapeutic modulation of auto-antibodies. We first discovered a small molecule, CRANAD-17, that enhanced the binding of an antibody to amyloid beta (Aβ), one of the major hallmarks of Alzheimer's disease, by stable triplex formation. Next, we found several small molecules that altered antibody-epitope interactions of tau and PD-L1 proteins, demonstrating the generality of this phenomenon. We report a new screening technology for ligand discovery, screening platform based on epitope alteration for drug discovery (SPEED), which is label-free for both the antibody and small molecule. SPEED, applied to an Aβ antibody, led to the discovery of a small molecule, GNF5837, that inhibits Aβ aggregation and another, obatoclax, that binds Aβ plaques and can serve as a fluorescent reporter in brain slices of AD mice. We also found a small molecule that altered the binding between Aβ and auto-antibodies from AD patient serum. SPEED reveals the sensitivity of antibody-epitope interactions to perturbation by small molecules and will have multiple applications in biotechnology and drug discovery.
PubMed: 35919434
DOI: 10.1039/d2sc02819k -
Oral Oncology Sep 2022The purpose of this review was to summarise available literature concerning the anticancer effects of both putative and validated BH3-mimetics in head and neck squamous... (Review)
Review
The purpose of this review was to summarise available literature concerning the anticancer effects of both putative and validated BH3-mimetics in head and neck squamous cell carcinomas. A literature search was performed and studies assessing malignant cell lines, xenograft models, and/or humans were considered eligible. A total of 501 studies were identified, of which 40 were included. One phase-II clinical trial assessing gossypol (combined with docetaxel) was found. The remaining 39 preclinical studies investigated cell lines and/or xenograft models involving the use of six validated BH3-mimetics (A-1210477, A-1331852, ABT-737, navitoclax, S63845, venetoclax) and six putative BH3-mimetics (ApoG2, gossypol, obatoclax, sabutoclax, TW-37, and YC137). In preclinical settings, most validated BH3-mimetics were capable of inducing apoptosis (in-vitro) and tumour growth inhibition (in-vivo). The majority of putative BH3-mimetics were also capable of inducing cell death, although important off-target effects, such as autophagy induction, were also described. Combinations with conventional anticancer drugs, ionising radiation, or multiple BH3-mimetics generally resulted in enhanced anticancer effects, such as increased sensitivity to apoptotic stimuli, especially considering some cell lines that showed resistance to either treatment alone. In conclusion, although clinical data are still insufficient to evaluate the anticancer effects of BH3-mimetics in head and neck squamous cell carcinomas, promising results in preclinical settings were observed concerning induction of cell death and inhibition of tumour growth. Therefore, further clinical trials are highly encouraged.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Gossypol; Head and Neck Neoplasms; Humans; Proto-Oncogene Proteins c-bcl-2; Squamous Cell Carcinoma of Head and Neck
PubMed: 35816876
DOI: 10.1016/j.oraloncology.2022.105979 -
ChemMedChem Aug 2022Multidrug resistant (MDR) bacteria are an increasing public health problem. One promising alternative to the development of new antibiotics is the use of antibiotic...
Multidrug resistant (MDR) bacteria are an increasing public health problem. One promising alternative to the development of new antibiotics is the use of antibiotic adjuvants, which would allow the continued use of FDA-approved antibiotics that have been rendered ineffective due to resistance. Herein, we report a series of dipyrrins and pyrrole derivatives designed as analogues of prodigiosin and obatoclax, several of which potentiate the activity of colistin against Klebsiella pneumoniae, with lead compounds also potentiating colistin against Acinetobacter baumannii and Pseudomonas aeruginosa.
Topics: Acinetobacter baumannii; Adjuvants, Pharmaceutic; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Microbial Sensitivity Tests; Prodigiosin; Pseudomonas aeruginosa
PubMed: 35704751
DOI: 10.1002/cmdc.202200286