Small Molecular Oligopeptides Adorned with Tryptophan Residues as Potent Antitumor Agents: Design, Synthesis, Bioactivity Assay, Computational Prediction, and Experimental Validation

Journal of Chemical Information and Modeling, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Tryptophan participates in important life activities and is involved various metabolic processes. The indole aromatic binuclear ring structure tryptophan can engage diverse interactions, including π–π, π–alkyl, hydrogen bonding, cation−π, CH−π interactions with other side chains protein targets. These offer extensive opportunities for drug development. In this letter, we have designed synthesized a series of linear oligopeptides adorned residues identified their potential targets through artificial intelligence-assisted technology experimental verification. vitro bioactivity assays revealed that the containing Gly-Pro-Trp exhibited promising antitumor activity by inducing autophagy apoptosis. PharmMapper pharmacophore mapping approach, molecular docking, dynamics simulations together poly(ADP-ribose) polymerase 1 (PARP1), an enzyme associated chromatin regulation, as target compounds. Experimental biolayer interferometry (BLI) enzyme-linked immunosorbent assay (ELISA) verified could bind PARP1 influence expression levels. A quantitative structure–activity relationship has been established between chemical structures prepared compounds IC50 values. summary, research presents feasible approach exploring oligopeptide-based agents.

Язык: Английский

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The Anti-Cancer Effects of Arborinine from Ruta graveolens L. on Michigan Cancer Foundation-7 (MCF-7) Breast Cancer Cells: Inhibition of Cell Growth and Induction of Apoptosis

Cureus, Год журнала: 2025, Номер unknown

Опубликована: Янв. 25, 2025

Background: Arborinine, a plant-derived alkaloid, has shown potential cytotoxic effects against various cancer cell lines. This study aims to evaluate the cytotoxicity and apoptosis of arborinine on breast (Michigan Cancer Foundation-7 (MCF-7)) human embryonic kidney (HEK293) as normal Methods: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used assess inhibitory concentration 50% (IC50) after 24 48 hours treatment HEK293 MCF-7 lines with arborinine. Apoptosis evaluated through Annexin V/PI staining, gene expressions including BAX, BCL-2, P53, PARP, caspases (i.e., 3, 8, 9) were analyzed via quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, intracellular reactive oxygen species (ROS) levels measured using 2',7′-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence. Results: MTT results indicated dose-dependent reduction in viability for both cells following decreased significantly (P=0.038) at concentrations above 150 µg/mL, while IC50 50 µg/mL 25 hours, respectively. V staining revealed rates 9.36% untreated cells, increasing 52.3% post-treatment. Arborinine upregulated pro-apoptotic factors, downregulating BCL-2. increased ROS by approximately 1.3-fold glutathione (GSH) levels, enhancing superoxide dismutase (SOD) activity. Conclusion: shows that reduces induces modulating key apoptotic pathways. Its effectiveness lower cancerous highlights its promising therapeutic agent oncology.

Язык: Английский

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PARP1: A comprehensive review of its mechanisms, therapeutic implications and emerging cancer treatments

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2025, Номер unknown, С. 189282 - 189282

Опубликована: Фев. 1, 2025

Язык: Английский

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Self-Assembled Reduction-Responsive Nanoparticles Constructed from Dual Topoisomerase I/Ii Inhibitor for Efficient Breast Cancer Treatment

Опубликована: Янв. 1, 2025

Язык: Английский

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Combination of Antimalarial and CNS Drugs with Antineoplastic Agents in MCF-7 Breast and HT-29 Colon Cancer Cells: Biosafety Evaluation and Mechanism of Action

Biomolecules, Год журнала: 2022, Номер 12(10), С. 1490 - 1490

Опубликована: Окт. 16, 2022

Drug combination and drug repurposing are two strategies that allow to find novel oncological therapies, in a faster more economical process. In our previous studies, we developed model of using antineoplastic different repurposed drugs. We demonstrated the combinations doxorubicin (DOX) + artesunate, DOX chloroquine, paclitaxel (PTX) fluoxetine, PTX fluphenazine, benztropine induce significant cytotoxicity Michigan Cancer Foundation-7 (MCF-7) breast cancer cells. Furthermore, it was found 5-FU thioridazine 5-fluorouracil (5-FU) sertraline can synergistically reduction viability human colorectal adenocarcinoma cell line (HT-29). this study, aim (1) evaluate biosafety profile these for non-tumoral cells (2) determine their mechanism action To do so, fetal lung fibroblast (MRC-5) were incubated 48 h with all drugs, alone concentrations 0.25, 0.5, 1, 2, 4 times half-maximal inhibitory concentration (IC50). Cell morphology evaluated. Next, designed constructed microarray perform immunohistochemistry studies evaluation palmitoyl-protein thioesterase 1 (PPT1), Ki67, cleaved-poly (ADP-ribose) polymerase (cleaved-PARP), multidrug resistance-associated protein 2 (MRP2), P-glycoprotein (P-gp), nuclear factor-kappa-B (NF-kB) p65 expression. demonstrate cytotoxic safe at lower concentrations. is also PPT1 may have an important role combinations, as by ability decrease These results support use antimalarial central nervous system (CNS) drugs regimens chemotherapeutic agents; nevertheless, additional recommended further explore complete mechanisms action.

Язык: Английский

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Existing Evidence for the Repurposing of PARP-1 Inhibitors in Rare Demyelinating Diseases

Cancers, Год журнала: 2022, Номер 14(3), С. 687 - 687

Опубликована: Янв. 29, 2022

Over the past decade, Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have arisen as a novel and promising targeted therapy for breast cancer gene (BRCA)-mutated ovarian patients. Therapies targeting enzyme, PARP-1, since established their place maintenance drugs cancer. Here, we present existing evidence that implicates PARP-1 player in development progression of both malignancy demyelinating disease. These findings, together with proven clinical efficacy marketed success cancer, repurposing these diseases desirable therapeutic concept. Indeed, are noted to demonstrate neuroprotective effects disorders such multiple sclerosis Parkinson's disease, further supporting use demyelinating, neuroinflammatory, neurodegenerative diseases. In this review, discuss potential inhibitors, focus on rare particular, address possible examples leukodystrophies, which there paucity treatment options an urgent need approaches.

Язык: Английский

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Potential of uPAR, αvβ6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 3853 - 3853

Опубликована: Фев. 14, 2023

No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high homogenous expression in tumor tissue minimal normal is essential the development new molecular targets cancer. We investigated nine both primary matched metastatic 41 patients oral squamous cell carcinoma (OSCC) to assess their potential as imaging. intensity, proportion, homogeneity reaction neighboring non-cancerous was scored. intensity proportion were multiplied obtain total immunohistochemical (IHC) score ranging from 0-12. mean epithelium compared. rate urokinase-type plasminogen activator receptor (uPAR) (97%), integrin αvβ6 factor (86%) median immunostaining (interquartile range) tumors 6 (6-9), 12 (12-12), (2.5-7.5), respectively. For uPAR factor, staining significantly higher compared epithelium. uPAR, αvβ6, promising OSCC tumors, lymph node metastases, recurrences.

Язык: Английский

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Multi-stage structure-based virtual screening approach combining 3D pharmacophore, docking and molecular dynamic simulation towards the identification of potential selective PARP-1 inhibitors

BMC Chemistry, Год журнала: 2025, Номер 19(1)

Опубликована: Фев. 1, 2025

Abstract Presently, humanity is confronted with a range of diseases that have high death rates, especially those linked to cancerous growths. Several enzymes and proteins been discovered as highly attractive targets for cancer treatment. The PARP family consists 17 members plays crucial role in repairing DNA damage, which enables the survival cells. PARP-1 and, lesser extent, PARP-2 display above 90% activity response thereby distinguishing them apart from other family. Elevated levels were observed many types tumor cells, such breast, lung, ovarian, prostate, melanomas. In an attempt provide future guide developing selective inhibitors over minimize resulting side effects inhibitors, we constructed structure-based virtual screening approach (SBVS). Firstly. A 3D pharmacophore was based on interaction inhibitor compound IV . After that, database nearly 450,000 phthalimide-containing screened through validated pharmacophore, 165 compounds retrieved. retrieved docked into active site where only 5 MWGS-1-5 achieved favorable docking score than reference (-16.8 Kcal/mol). Redocking five should excellent selectivity PARP-2, MWGS-1 Further endorsement via molecular dynamics has proven higher affinity towards PARP-1- RMSD values 1.42 2.8 Å, respectively.

Язык: Английский

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Synthetic lethality between BRCA1 deficiency and poly(ADP-ribose) polymerase inhibition is modulated by processing of endogenous oxidative DNA damage

Nucleic Acids Research, Год журнала: 2019, Номер 47(17), С. 9132 - 9143

Опубликована: Июль 12, 2019

Abstract Poly(ADP-ribose) polymerases (PARPs) facilitate the repair of DNA single-strand breaks (SSBs). When PARPs are inhibited, unrepaired SSBs colliding with replication forks give rise to cytotoxic double-strand breaks. These normally rescued by homologous recombination (HR), but, in cells suboptimal HR, PARP inhibition leads genomic instability and cell death, a phenomenon currently exploited therapy ovarian cancers BRCA1/2 mutation carriers. In spite their promise, resistance inhibitors (PARPis) has already emerged. order identify possible underlying causes resistance, we set out endogenous source damage that activates PARPs. We argued if toxicity PARPis is indeed caused SSBs, these must arise spontaneously, because used as single agents. now show significant contributor PARPi oxygen metabolism. While BRCA1-depleted or -mutated were hypersensitive clinically approved olaparib, its was significantly attenuated depletion OGG1 MYH glycosylases, well treatment reactive species scavengers, growth under hypoxic conditions chemical inhibition. Thus, clinical may emerge simply through reduced efficiency oxidative repair.

Язык: Английский

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Targeting Nuclear NAD+ Synthesis Inhibits DNA Repair, Impairs Metabolic Adaptation and Increases Chemosensitivity of U-2OS Osteosarcoma Cells

Cancers, Год журнала: 2020, Номер 12(5), С. 1180 - 1180

Опубликована: Май 7, 2020

Osteosarcoma (OS) is the most common bone tumor in children and adolescents. Modern OS treatment, based on combination of neoadjuvant chemotherapy (cisplatin + doxorubicin methotrexate) with subsequent surgical removal primary metastases, has dramatically improved overall survival patients. However, further research needed to identify new therapeutic targets. Here we report that expression level nuclear NAD synthesis enzyme, nicotinamide mononucleotide adenylyltransferase-1 (NMNAT1), increases U-2OS cells upon exposure DNA damaging agents, suggesting involvement enzyme damage response. Moreover, genetic inactivation NMNAT1 sensitizes osteosarcoma cisplatin, doxorubicin, or a these two treatments. Increased cisplatin-induced cell death NMNAT1−/− showed features both apoptosis necroptosis, as indicated by protective effect caspase-3 inhibitor z-DEVD-FMK necroptosis necrostatin-1. Activation sensor poly(ADP-ribose) polymerase 1 (PARP1), major consumer NAD+ nucleus, was fully blocked inactivation, leading increased (phospho-H2AX foci). The PARP inhibitor, olaparib, sensitized wild type but not anti-clonogenic effects, impaired PARP1 activity important for chemosensitization. Cisplatin-induced also characterized marked drop cellular ATP levels mitochondrial respiratory reserve capacity, highlighting central role compromised bioenergetics chemosensitization inactivation. displayed markedly higher sensitivity cisplatin when grown spheroids 3D culture. In summary, our work provides first evidence promising target possibly other tumors well.

Язык: Английский

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