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1.
Drug Dev Res ; 85(4): e22218, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38825827

ABSTRACT

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).


Subject(s)
Antineoplastic Agents , Benzimidazoles , Molecular Docking Simulation , Oxadiazoles , Vascular Endothelial Growth Factor Receptor-2 , Humans , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism , Oxadiazoles/pharmacology , Oxadiazoles/chemistry , Oxadiazoles/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Cell Line, Tumor , Structure-Activity Relationship , Drug Screening Assays, Antitumor , Vascular Endothelial Growth Factor A/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Cell Proliferation/drug effects
2.
Drug Des Devel Ther ; 18: 1833-1853, 2024.
Article in English | MEDLINE | ID: mdl-38828018

ABSTRACT

Purpose: Given the potent immunostimulatory effects of bacterial outer membrane vesicles (OMVs) and the significant anti-colon tumor properties of Parabacteroides distasonis (Pd), this study aimed to elucidate the role and potential mechanisms of Pd-derived OMVs (Pd-OMVs) against colon cancer. Methods: This study isolated and purified Pd-OMVs from Pd cultures and assessed their characteristics. The effects of Pd-OMVs on CT26 cell uptake, proliferation, and invasion were investigated in vitro. In vivo, a CT26 colon tumor model was used to investigate the anti-colon tumor effects and underlying mechanisms of Pd-OMVs. Finally, we evaluated the biosafety of Pd-OMVs. Results: Purified Pd-OMVs had a uniform cup-shaped structure with an average size of 165.5 nm and a zeta potential of approximately -9.56 mV, and their proteins were associated with pathways related to immunity and apoptosis. In vitro experiments demonstrated that CT26 cells internalized the Pd-OMVs, resulting in a significant decrease in their proliferation and invasion abilities. Further in vivo studies confirmed the accumulation of Pd-OMVs in tumor tissues, which significantly inhibited the growth of colon tumors. Mechanistically, Pd-OMVs increased the expression of CXCL10, promoting infiltration of CD8+ T cells into tumor tissues and expression of pro-inflammatory factors TNF-α, IL-1ß, and IL-6. Notably, Pd-OMVs demonstrated a high level of biosafety. Conclusion: This paper elucidates that Pd-OMVs can exert significant anti-colon tumor effects by upregulating the expression of the chemokine CXCL10, thereby increasing the infiltration of CD8+ T cells into tumors and enhancing antitumor immune responses. This suggests that Pd-OMVs may be developed as a novel nanoscale potent immunostimulant with great potential for application in tumor immunotherapy. As well as developed as a novel nano-delivery carrier for combination with other antitumor drugs.


Subject(s)
CD8-Positive T-Lymphocytes , Cell Proliferation , Chemokine CXCL10 , Colonic Neoplasms , Mice, Inbred BALB C , Colonic Neoplasms/immunology , Colonic Neoplasms/pathology , Colonic Neoplasms/drug therapy , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , Mice , Cell Proliferation/drug effects , Chemokine CXCL10/metabolism , Chemokine CXCL10/immunology , Bacterial Outer Membrane/immunology , Bacterial Outer Membrane/drug effects , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Humans , Neoplasms, Experimental/pathology , Neoplasms, Experimental/immunology , Neoplasms, Experimental/drug therapy , Drug Screening Assays, Antitumor , Tumor Cells, Cultured
3.
Drug Res (Stuttg) ; 74(5): 227-240, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38830371

ABSTRACT

PURPOSE: Cancer is the second leading cause of death globally and is responsible for an estimated 9.6 million deaths in 2018. Globally, about 1 in 6 deaths is due to cancer and the chemotherapeutic drugs available have high toxicity and have reported side effects hence, there is a need for the synthesis of novel drugs in the treatment of cancer. METHODS: The current research work dealt with the synthesis of a series of 3-(3-acetyl-2-oxoquinolin-1-(2H)-yl-2-(substitutedphenyl)thiazolidin-4-one (Va-j) derivatives and evaluation of their in-vitro anticancer activity. All the synthesized compounds were satisfactorily characterized by IR and NMR data. Compounds were further evaluated for their in-vitro anticancer activity against A-549 (lung cancer) cell lines. The in-vitro anticancer activity was based upon the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay method. RESULTS: The synthesized compounds exhibited satisfactory anticancer properties against the A-549 cell line. The compound (VH): showed the highest potency amongst the tested derivatives against the A-549 cell line with IC50 values of 100 µg/ml respectively and was also found to be more potent than Imatinib (150 µg/ml) which was used as a standard drug. Molecular docking studies of the titled compounds (Va-j) were carried out using AutoDock Vina/PyRx software. The synthesized compounds exhibited well-conserved hydrogen bonds with one or more amino acid residues in the active pocket of the EGFRK tyrosine kinase domain (PDB 1m17). CONCLUSION: Among all the synthesized analogues, the binding affinity of the compound (Vh) was found to be higher than other synthesized derivatives and a molecular dynamics simulation study explored the stability of the docked complex system.


Subject(s)
Antineoplastic Agents , ErbB Receptors , Lung Neoplasms , Molecular Docking Simulation , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Cell Line, Tumor , A549 Cells , Thiazolidines/pharmacology , Thiazolidines/chemistry , Thiazolidines/chemical synthesis , Drug Screening Assays, Antitumor , Cell Proliferation/drug effects
4.
J Cell Mol Med ; 28(9): e18374, 2024 May.
Article in English | MEDLINE | ID: mdl-38722288

ABSTRACT

The majority of advanced breast cancers exhibit strong aggressiveness, heterogeneity, and drug resistance, and currently, the lack of effective treatment strategies is one of the main challenges that cancer research must face. Therefore, developing a feasible preclinical model to explore tailored treatments for refractory breast cancer is urgently needed. We established organoid biobanks from 17 patients with breast cancer and characterized them by immunohistochemistry (IHC) and next generation sequencing (NGS). In addition, we in the first combination of patient-derived organoids (PDOs) with mini-patient-derived xenografts (Mini-PDXs) for the rapid and precise screening of drug sensitivity. We confirmed that breast cancer organoids are a high-fidelity three-dimension (3D) model in vitro that recapitulates the original tumour's histological and genetic features. In addition, for a heavily pretreated patient with advanced drug-resistant breast cancer, we combined PDO and Mini-PDX models to identify potentially effective combinations of therapeutic agents for this patient who were alpelisib + fulvestrant. In the drug sensitivity experiment of organoids, we observed changes in the PI3K/AKT/mTOR signalling axis and oestrogen receptor (ER) protein expression levels, which further verified the reliability of the screening results. Our study demonstrates that the PDO combined with mini-PDX model offers a rapid and precise drug screening platform that holds promise for personalized medicine, improving patient outcomes and addressing the urgent need for effective therapies in advanced breast cancer.


Subject(s)
Breast Neoplasms , Organoids , Precision Medicine , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Female , Organoids/drug effects , Organoids/pathology , Organoids/metabolism , Precision Medicine/methods , Animals , Xenograft Model Antitumor Assays , Mice , Drug Resistance, Neoplasm/drug effects , Drug Screening Assays, Antitumor/methods , Middle Aged
5.
Cell Biochem Funct ; 42(4): e4027, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38715184

ABSTRACT

Bioactive phytocompounds are crucial components in all plants. Since the time of traditional medicine, the utilization of plants has been grounded in the potential of these bioactive compounds to treat or manage specific illnesses. These natural bioactive compounds have sparked growing interest in employing medicinal plants for addressing various conditions, such as inflammatory diseases, diabetes, and cancer. This study focuses on assessing the qualitative phytochemical composition, antioxidant potential, and cytotoxic effects of blueberry (Vaccinium sect. Cyanococcus) extract using three different solvents, namely water, ethanol, and methanol. The extract exhibited notable antioxidant activities, as evidenced by DPPH and H2O2 free radical scavenging assays. The cell viability assay also demonstrated cell growth inhibition in A549 cells. Furthermore, nine specific phytocompounds sourced from existing literature were selected for molecular docking studies against CDK6 and, AMPK key protein kinases which enhance the cancer progression. The molecular docking results also revealed favorable binding scores, with a high score of -9.5 kcal/mol in CDK6 protein and a maximum score of AMPK with targets of -8.8 kcal/mol. The selected phytocompounds' pharmacodynamic properties such as ADMET also supported the study. Furthermore, rutin stated that pre-dominantly present in blueberry plants shows a potent cytotoxicity effect in A549 cells. Functional annotations by bioinformatic analysis for rutin also revealed the strong enrichment in the involvement of PI3K/AKT1/STAT, and p53 signaling pathways. Based on this analysis, the identified rutin and other compounds hold a promising anticancer activity. Overall, the comprehensive evaluation of both in vitro and in silico data suggests that the Vaccinium sect. Cyanococcus extract could serve as a valuable source of pharmaceutical agents and may prove effective in future therapeutic applications.


Subject(s)
Blueberry Plants , Cell Proliferation , ErbB Receptors , Oxidative Stress , Plant Extracts , STAT3 Transcription Factor , Signal Transduction , Tumor Suppressor Protein p53 , Humans , Plant Extracts/pharmacology , Plant Extracts/chemistry , Blueberry Plants/chemistry , Oxidative Stress/drug effects , STAT3 Transcription Factor/metabolism , Tumor Suppressor Protein p53/metabolism , A549 Cells , Signal Transduction/drug effects , Cell Proliferation/drug effects , ErbB Receptors/metabolism , Interleukin-6/metabolism , Molecular Docking Simulation , Lung Neoplasms/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Cell Survival/drug effects , Antioxidants/pharmacology , Antioxidants/chemistry , Antioxidants/metabolism , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Drug Screening Assays, Antitumor
6.
J Enzyme Inhib Med Chem ; 39(1): 2343352, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38700244

ABSTRACT

In the last decade, an increasing interest in compounds containing pyrazolo[4,3-e][1,2,4]triazine moiety is observed. Therefore, the aim of the research was to synthesise a novel sulphonyl pyrazolo[4,3-e][1,2,4]triazines (2a, 2b) and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives (3a, 3b) to assess their anticancer activity. The MTT assay showed that 2a, 2b, 3a, 3b have stronger cytotoxic activity than cisplatin in both breast cancer cells (MCF-7 and MDA-MB-231) and exhibited weaker effect on normal breast cells (MCF-10A). The obtained results showed that the most active compound 3b increased apoptosis via caspase 9, caspase 8, and caspase 3/7. It is worth to note that compound 3b suppressed NF-κB expression and promoted p53, Bax, and ROS which play important role in activation of apoptosis. Moreover, our results confirmed that compound 3b triggers autophagy through increased formation of autophagosomes, expression of beclin-1 and mTOR inhibition. Thus, our study defines a possible mechanism underlying 3b-induced anti-cancer activity against breast cancer cell lines.


Subject(s)
Antineoplastic Agents , Apoptosis , Breast Neoplasms , Cell Proliferation , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Sulfonamides , Triazines , Humans , Triazines/pharmacology , Triazines/chemistry , Triazines/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Structure-Activity Relationship , Sulfonamides/pharmacology , Sulfonamides/chemistry , Sulfonamides/chemical synthesis , Molecular Structure , Cell Proliferation/drug effects , Apoptosis/drug effects , Tumor Cells, Cultured , Pyrazoles/pharmacology , Pyrazoles/chemistry , Pyrazoles/chemical synthesis , Female , Cell Line, Tumor , Spheroids, Cellular/drug effects
8.
Molecules ; 29(9)2024 Apr 28.
Article in English | MEDLINE | ID: mdl-38731532

ABSTRACT

A series of flavanols were synthesized to assess their biological activity against human non-small cell lung cancer cells (A549). Among the sixteen synthesized compounds, it was observed that compounds 6k (3.14 ± 0.29 µM) and 6l (0.46 ± 0.02 µM) exhibited higher potency compared to 5-fluorouracil (5-Fu, 4.98 ± 0.41 µM), a clinical anticancer drug which was used as a positive control. Moreover, compound 6l (4'-bromoflavonol) markedly induced apoptosis of A549 cells through the mitochondrial- and caspase-3-dependent pathways. Consequently, compound 6l might be developed as a candidate for treating or preventing lung cancer.


Subject(s)
Antineoplastic Agents , Apoptosis , Flavonols , Humans , Flavonols/pharmacology , Flavonols/chemical synthesis , Flavonols/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , A549 Cells , Caspase 3/metabolism , Cell Proliferation/drug effects , Structure-Activity Relationship , Molecular Structure , Fluorouracil/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Drug Screening Assays, Antitumor , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Cell Line, Tumor
9.
Molecules ; 29(9)2024 Apr 29.
Article in English | MEDLINE | ID: mdl-38731537

ABSTRACT

The fungal genus Trichoderma is a rich source of structurally diverse secondary metabolites with remarkable pharmaceutical properties. The chemical constituents and anticancer activities of the marine-derived fungus Trichoderma lixii have never been investigated. In this study, a bioactivity-guided investigation led to the isolation of eleven compounds, including trichodermamide A (1), trichodermamide B (2), aspergillazine A (3), DC1149B (4), ergosterol peroxide (5), cerebrosides D/C (6/7), 5-hydroxy-2,3-dimethyl-7-methoxychromone (8), nafuredin A (9), and harzianumols E/F (10/11). Their structures were identified by using various spectroscopic techniques and compared to those in the literature. Notably, compounds 2 and 5-11 were reported for the first time from this species. Evaluation of the anticancer activities of all isolated compounds was carried out. Compounds 2, 4, and 9 were the most active antiproliferative compounds against three cancer cell lines (human myeloma KMS-11, colorectal HT-29, and pancreas PANC-1). Intriguingly, compound 4 exhibited anti-austerity activity with an IC50 of 22.43 µM against PANC-1 cancer cells under glucose starvation conditions, while compound 2 did not.


Subject(s)
Antineoplastic Agents , Trichoderma , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Humans , Trichoderma/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Molecular Structure , Aquatic Organisms/chemistry , Drug Screening Assays, Antitumor
10.
Drug Des Devel Ther ; 18: 1531-1546, 2024.
Article in English | MEDLINE | ID: mdl-38737331

ABSTRACT

Purpose: Lung adenocarcinoma currently ranks the leading causes of cancer-related mortality worldwide. Many anti-inflammation herbs, like tetramethylpyrazine, have shown their anti-tumor potentials. Here, we evaluated the role of a novel chalcone derivative of tetramethylpyrazine ((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1, HCTMPPK) in lung adenocarcinoma. Methods: The effects of HCTMPPK on cell proliferation, apoptosis, and invasion were investigated by in-vitro assays, including CCK-8, colony formation assay, flow cytometry, transwell assay, and wound-healing assay. The therapeutic potential of HCTMPPK in vivo was evaluated in xenograft mice. To figure out the target molecules of HCTMPPK, a network pharmacology approach and molecular docking studies were employed, and subsequent experiments were conducted to confirm these candidate molecules. Results: HCTMPPK effectively suppressed the proliferative activity and migration, as well as enhanced the apoptosis of A549 cells in a concentration-dependent manner. Consistent with this, tumor growth was inhibited by HCTMPPK significantly in vivo. Regarding the mechanisms, HCTMPPK down-regulated Bcl-2 and MMP-9 and up-regulating Bax and cleaved-caspase-3. Subsequently, we identified 601 overlapping DEGs from LUAD patients in TCGA and GEO database. Then, 15 hub genes were identified by PPI network and CytoHubba. Finally, MELK was verified to be the HCTMPPK targeted site, through the molecular docking studies and validation experiments. Conclusion: Overall, our study indicates HCTMPPK as a potential MELK inhibitor and may be a promising candidate for the therapy of lung cancer.


Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Down-Regulation , Drug Screening Assays, Antitumor , Lung Neoplasms , Pyrazines , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Pyrazines/pharmacology , Pyrazines/chemistry , Cell Proliferation/drug effects , Animals , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Down-Regulation/drug effects , Chalcone/pharmacology , Chalcone/chemistry , Molecular Structure , Dose-Response Relationship, Drug , Structure-Activity Relationship , Molecular Docking Simulation , Mice, Nude , Mice, Inbred BALB C , A549 Cells , Cell Movement/drug effects , Chalcones/pharmacology , Chalcones/chemistry , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism , Tumor Cells, Cultured
11.
Nat Prod Res ; 38(11): 1864-1873, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38739563

ABSTRACT

Phytochemical studies of the stems and leaves of Stephania dielsiana Y.C.Wu yielded two new aporphine alkaloids (1 and 5), along with six known alkaloids (2-4 and 6-8). Their structures were characterised based on analyses of spectroscopic data, including one- and two-dimensional nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS). The cytotoxic activities of the isolated compounds against a small panel of tumour cell lines were assessed by MTS assay. Interestingly, compound 2 exhibited particularly strong cytotoxic activities against HepG2, MCF7 and OVCAR8 cancer cell lines, with IC50 values of 3.20 ± 0.18, 3.10 ± 0.06 and 3.40 ± 0.007 µM, respectively. Furthermore, molecular docking simulations were carried out to explore the interactions and binding mechanisms of the most active compound (compound 2) with proteins. Our results contribute to understanding the secondary metabolites produced by S. dielsiana and provide a scientific rationale for further investigations of cytotoxicity of this valuable medicinal plant.


Subject(s)
Alkaloids , Antineoplastic Agents, Phytogenic , Aporphines , Molecular Docking Simulation , Plant Leaves , Plant Stems , Stephania , Aporphines/chemistry , Aporphines/pharmacology , Humans , Plant Leaves/chemistry , Plant Stems/chemistry , Alkaloids/chemistry , Alkaloids/pharmacology , Stephania/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Molecular Structure , Cell Line, Tumor , Hep G2 Cells , MCF-7 Cells , Drug Screening Assays, Antitumor , Magnetic Resonance Spectroscopy , Plants, Medicinal/chemistry
12.
Bioorg Chem ; 147: 107412, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38696845

ABSTRACT

The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.


Subject(s)
Antineoplastic Agents , DNA Topoisomerases, Type I , Fingolimod Hydrochloride , Molecular Docking Simulation , Topoisomerase I Inhibitors , Humans , Fingolimod Hydrochloride/pharmacology , Fingolimod Hydrochloride/chemistry , Fingolimod Hydrochloride/chemical synthesis , DNA Topoisomerases, Type I/metabolism , DNA Topoisomerases, Type I/chemistry , Topoisomerase I Inhibitors/pharmacology , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/chemical synthesis , Molecular Structure , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Cell Proliferation/drug effects , Molecular Dynamics Simulation , MCF-7 Cells
13.
ACS Appl Bio Mater ; 7(5): 3431-3440, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38697834

ABSTRACT

Light-induced release of cisplatin from Pt(IV) prodrugs represents a promising approach for precise control over the antiproliferative activity of Pt-based chemotherapeutic drugs. This method has the potential to overcome crucial drawbacks of conventional cisplatin therapy, such as high general toxicity toward healthy organs and tissues. Herein, we report two Pt(IV) prodrugs with BODIPY-based photoactive ligands Pt-1 and Pt-2, which were designed using carbamate and triazole linkers, respectively. Both prodrugs demonstrated the ability to release cisplatin under blue light irradiation without the requirement of an external reducing agent. Dicarboxylated Pt-2 prodrug turned out to be more stable in the dark and more sensitive to light than its monocarbamate Pt-1 counterpart; these observations were explained using DFT calculations. The investigation of the photoreduction mechanism of Pt-1 and Pt-2 prodrugs using DFT modeling and ΔG0 PET estimation suggests that the photoinduced electron transfer from the singlet excited state of the BODIPY axial ligand to the Pt(IV) center is the key step in the light-induced release of cisplatin from the complexes. Cytotoxicity studies demonstrated that both prodrugs were nontoxic in the dark and toxic to MCF-7 cells under low-dose irradiation with blue light, and the observed effect was solely due to the cisplatin release from the Pt(IV) prodrugs. Our research presents an elegant synthetic approach to light-activated Pt(IV) prodrugs and presents findings that may contribute to the future rational design of photoactivatable Pt(IV) prodrugs.


Subject(s)
Antineoplastic Agents , Drug Screening Assays, Antitumor , Light , Prodrugs , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/chemical synthesis , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Molecular Structure , Materials Testing , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Biocompatible Materials/chemical synthesis , Cell Survival/drug effects , Cell Proliferation/drug effects , Cisplatin/pharmacology , Cisplatin/chemistry , Particle Size , Boron Compounds/chemistry , Boron Compounds/pharmacology , Boron Compounds/chemical synthesis , Photochemical Processes , Density Functional Theory
14.
ACS Appl Bio Mater ; 7(5): 3403-3413, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38700026

ABSTRACT

The delivery of drugs to the brain in the therapy of diseases of the central nervous system (CNS) remains a continuing challenge because of the lack of delivery systems that can cross the blood-brain barrier (BBB). Therefore, there is a need to develop an innovative delivery method for the treatment of CNS diseases. Thus, we have investigated the interaction of γ-aminobutyric acid (GABA) and S-(-)-γ-amino-α-hydroxybutyric acid (GAHBA) with the GABA receptor by performing a docking study. Both GABA and GAHBA show comparable binding affinities toward the receptor. In this study, we developed surface-modified solid lipid nanoparticles (SLNs) using GAHBA-derived lipids that can cross the BBB. CLB-loaded SLNs were characterized by a number of methods including differential scanning calorimetry, dynamic light scattering, UV-vis spectroscopy, and transmission electron microscopy. The blank and CLB-loaded SLN suspensions were found to exhibit good storage stability. Also, the SLNs showed a higher encapsulation efficiency for CLB drugs. In vitro release kinetics of CLB at physiological temperature was also investigated. The results of the in vitro cell cytotoxicity assay and flow cytometry studies in the human glioma U87MG cell line and human prostate cancer PC3 cell line suggested a higher efficacy of the GAHBA-modified CLB-loaded SLNs in U87MG cells. The transcription level of GABA receptor expression in the target organ and cell line was analyzed by a reverse transcription polymerase chain reaction study. The in vivo biodistribution and brain uptake in C57BL6 mice and SPECT/CT imaging in Wistar rats investigated using 99mTc-labeled SLN and autoradiography suggest that the SLNs have an increasing brain uptake. We have demonstrated the delivery of the anticancer drug chlorambucil (CLB) to glioma.


Subject(s)
Brain , Chlorambucil , Lipids , Nanoparticles , Particle Size , Chlorambucil/chemistry , Chlorambucil/pharmacology , Chlorambucil/administration & dosage , Nanoparticles/chemistry , Animals , Brain/metabolism , Lipids/chemistry , Humans , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Materials Testing , Surface Properties , Mice , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Drug Delivery Systems , Rats , Drug Carriers/chemistry , Cell Line, Tumor
15.
ACS Appl Bio Mater ; 7(5): 3337-3345, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38700956

ABSTRACT

A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS2@mSiO2-RhB entails an ReS2 hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS2 nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat. These ReS2 nanospheres were generated by a hydrothermal synthesis process leading to the self-assembly of few-layered ReS2 nanosheets. The mesoporous silica shell was further coated on the surface of the ReS2 nanospheres through a surfactant-templating sol-gel approach to provide accessible mesopores for drug uploading. A fluorescent dye (Rhodamine B) was covalently attached to silica precursors and incorporated during synthesis in the mesoporous silica walls toward conferring imaging capability to the nanocarrier. Doxorubicin (DOX), a known cancer drug, was used in a proof-of-concept study to assess the material's ability to function as a drug delivery carrier. While the silica pores are not capped, the drug molecule loading and release take advantage of the pH-governed electrostatic interactions between the drug and silica wall. The ReS2@mSiO2-RhB enabled a drug loading content as high as 19.83 mg/g doxorubicin. The ReS2@mSiO2-RhB-DOX nanocarrier's cumulative drug release rate at pH values that simulate physiological conditions showed significant pH responsiveness, reaching 59.8% at pH 6.8 and 98.5% and pH 5.5. The in vitro testing using HeLa cervical cancer cells proved that ReS2@mSiO2-RhB-DOX has a strong cancer eradication ability upon irradiation with an NIR laser owing to the combined drug delivery and photothermal effect. The results highlight the potential of ReS2@mSiO2-RhB nanoparticles for combined cancer therapy in the future.


Subject(s)
Doxorubicin , Drug Liberation , Drug Screening Assays, Antitumor , Materials Testing , Nanoparticles , Particle Size , Photothermal Therapy , Rhenium , Silicon Dioxide , Silicon Dioxide/chemistry , Humans , Doxorubicin/pharmacology , Doxorubicin/chemistry , Hydrogen-Ion Concentration , Nanoparticles/chemistry , Rhenium/chemistry , Rhenium/pharmacology , Disulfides/chemistry , Porosity , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Biocompatible Materials/chemical synthesis , Cell Survival/drug effects , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Drug Carriers/chemistry , HeLa Cells
16.
Bioorg Chem ; 147: 107422, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38705106

ABSTRACT

Two acylhydrazone based zinc(II) complexes [Zn(HL)2Cl2(CH3OH)2] (Zn1) and [ZnL(AC)]2 (Zn2) were synthesized from 3-(1-(salicyloylhydrazono)ethyl) pyridine (HL). Single crystal X-ray structure analyses showed that complexes Zn1 and Zn2 have a zero-dimensional monomer or dimer structure. Antiproliferative activity studies revealed that Zn1 and Zn2 are both more effective against A549 cells than cisplatin. The results of the reactive oxygen species (ROS) generation assay on A549 cells showed that both Zn1 and Zn2 induced apoptosis through ROS accumulation. The apoptosis-inducing and cell cycle arrest effects of Zn1 and Zn2 on A549 cells indicated that the antitumor effect was achieved through apoptosis induction and inhibition of DNA synthesis by blocking the G0/G1 phase of the cell cycle. What's more, the results of wound-healing assay showed that Zn1 and Zn2 could inhibit the migration of A549 cells. Western blot analysis further demonstrated that Zn1 and Zn2 induced cell apoptosis through the mitochondrial pathway, in which process, the expression level of cytochrome C, cleaved-PARP, cleaved-caspase 3 and cleaved-caspase 9 proteins increased while pro-caspase 3 and pro-caspase 9 expression decreased. In vivo anticancer evaluation demonstrated that both Zn1 and Zn2 complexes effectively inhibited tumor growth without causing significant toxicity in systemic organs.


Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Coordination Complexes , Drug Screening Assays, Antitumor , Hydrazones , Lung Neoplasms , Zinc , Animals , Mice , A549 Cells , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Apoptosis/drug effects , Cell Proliferation/drug effects , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis , Dose-Response Relationship, Drug , Hydrazones/chemistry , Hydrazones/pharmacology , Hydrazones/chemical synthesis , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism , Reactive Oxygen Species/metabolism , Structure-Activity Relationship , Zinc/chemistry , Zinc/pharmacology
17.
ACS Appl Bio Mater ; 7(5): 3190-3201, 2024 May 20.
Article in English | MEDLINE | ID: mdl-38709861

ABSTRACT

We report an near-infrared (NIR)-trackable and therapeutic liposome with skin tumor specificity. Liposomes with a hydrodynamic diameter of ∼20 nm are tracked under the vein visualization imaging system in the presence of loaded paclitaxel and NIR-active agents. The ability to track liposome nanocarriers is recorded on the tissue-mimicking phantom model and in vivo mouse veins after intravenous administration. The trackable liposome delivery provides in vitro and in vivo photothermal heat (∼40 °C) for NIR-light-triggered area-specific chemotherapeutic release. This approach can be linked with a real-time vein-imaging system to track and apply area-specific local heat, which hitchhikes liposomes from the vein and finally releases them at the tumor site. We conducted studies on mice skin tumors that indicated the disappearance of tumors visibly and histologically (H&E stains). The ability of nanocarriers to monitor after administration is crucial for improving the effectiveness and specificity of cancer therapy, which could be achieved in the trackable delivery system.


Subject(s)
Infrared Rays , Liposomes , Paclitaxel , Precision Medicine , Skin Neoplasms , Liposomes/chemistry , Animals , Mice , Skin Neoplasms/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/therapy , Paclitaxel/chemistry , Paclitaxel/administration & dosage , Paclitaxel/pharmacology , Materials Testing , Biocompatible Materials/chemistry , Particle Size , Humans , Drug Delivery Systems , Drug Screening Assays, Antitumor
18.
J Biol Inorg Chem ; 29(3): 331-338, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38717473

ABSTRACT

Two new lanthanide-complexes based on the 5-nitropicolinate ligand (5-npic) were obtained and fully characterized. Single-crystal X-ray diffraction revealed that these compounds are isostructural to a Dy-complex, previously published by us, based on dinuclear monomers link together with an extended hydrogen bond network, providing a final chemical formula of [Ln2(5-npic)6(H2O)4]·(H2O)2, where Ln = Dy (1), Gd (2), and Tb (3). Preliminary photoluminescent studies exhibited a ligand-centered emission for all complexes. The potential antitumoral activity of these materials was assayed in a prostatic cancer cell line (PC-3; the 2nd most common male cancerous disease), showing a significant anticancer activity (50-60% at 500 µg·mL-1). In turn, a high biocompatibility by both, the complexes and their precursors in human immunological HL-60 cells, was evidenced. In view of the strongest toxic effect in the tumoral cell line provided by the free 5-npic ligand (~ 40-50%), the overall anticancer complex performance seems to be triggered by the presence of this molecule.


Subject(s)
Antineoplastic Agents , Lanthanoid Series Elements , Picolinic Acids , Humans , Lanthanoid Series Elements/chemistry , Lanthanoid Series Elements/pharmacology , Picolinic Acids/chemistry , Picolinic Acids/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Coordination Complexes/chemical synthesis , Male , Drug Screening Assays, Antitumor , Models, Molecular , HL-60 Cells , Crystallography, X-Ray , Molecular Structure , Cell Line, Tumor , PC-3 Cells , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Cell Survival/drug effects , Cell Proliferation/drug effects
19.
J Biol Inorg Chem ; 29(3): 303-314, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38727821

ABSTRACT

This study demonstrates the potential of sono-photodynamic therapy as an effective approach for enhancing singlet oxygen generation using the synthesized Schiff-base diaxially substituted silicon phthalocyanines. In photochemical studies, the singlet oxygen quantum yields (Φ∆) were determined as 0.43 for Si1a, 0.94 for Q-Si1a, 0.58 for S-Si1a, and 0.49 for B-Sia1. In sono-photochemical studies, the Φ∆ values were reached to 0.67 for Si1a, 1.06 for Q-Si1a, 0.65 for S-Si1a, and 0.67 for B-Sia1. In addition, this study demonstrates the therapeutic efficacy of phthalocyanines synthesized as sensitizers on the PC3 prostate cancer cell line through in vitro experiments. The application of these treatment modalities exhibited notable outcomes, leading to a substantial decrease in cell viability within the PC3 prostate cancer cell line. These findings highlight the potential of utilizing these synthesized phthalocyanines as promising therapeutic agents for prostate cancer treatment.


Subject(s)
Cell Survival , Indoles , Organosilicon Compounds , Prostatic Neoplasms , Schiff Bases , Singlet Oxygen , Humans , Indoles/chemistry , Indoles/pharmacology , Schiff Bases/chemistry , Schiff Bases/pharmacology , Male , Singlet Oxygen/metabolism , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Organosilicon Compounds/chemistry , Organosilicon Compounds/pharmacology , Cell Survival/drug effects , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Drug Screening Assays, Antitumor , PC-3 Cells , Photochemotherapy , Photochemical Processes , Cell Line, Tumor , Molecular Structure
20.
Drug Dev Res ; 85(4): e22197, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38751223

ABSTRACT

Although various approaches exist for treating cancer, chemotherapy continues to hold a prominent role in the management of this disease. Besides, microtubules serve as a vital component of the cellular skeleton, playing a pivotal role in the process of cell division making it an attractive target for cancer treatment. Hence, the scope of this work was adapted to design and synthesize new anti-tubulin tetrabromophthalimide hybrids (3-17) with colchicine binding site (CBS) inhibitory potential. The conducted in vitro studies showed that compound 16 displayed the lowest IC50 values (11.46 µM) at the FaDu cancer cell lines, whereas compound 17 exhibited the lowest IC50 value (13.62 µM) at the PC3 cancer cell line. However, compound 7b exhibited the lowest IC50 value (11.45 µM) at the MDA-MB-468 cancer cell line. Moreover, compound 17 was observed to be the superior antitumor candidate against all three tested cancer cell lines (MDA-MB-468, PC3, and FaDu) with IC50 values of 17.22, 13.15, and 13.62 µM, respectively. In addition, compound 17 showed a well-established upregulation of apoptotic markers (Caspases 3, 7, 8, and 9, Bax, and P53). Moreover, compound 17 induced downregulation of the antiapoptotic markers (MMP2, MMP9, and BCL-2). Furthermore, the colchicine binding site inhibition assay showed that compounds 15a and 17 exhibited particularly significant inhibitory potentials, with IC50 values of 23.07 and 4.25 µM, respectively, compared to colchicine, which had an IC50 value of 3.89 µM. Additionally, cell cycle analysis was conducted, showing that compound 17 could prompt cell cycle arrest at both the G0-G1 and G2-M phases. On the other hand, a molecular docking approach was applied to investigate the binding interactions of the examined candidates compared to colchicine towards CBS of the ß-tubulin subunit. Thus, the synthesized tetrabromophthalimide hybrids can be regarded as outstanding anticancer candidates with significant apoptotic activity.


Subject(s)
Antineoplastic Agents , Apoptosis , Drug Design , Phthalimides , Tubulin Modulators , Humans , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Phthalimides/chemical synthesis , Phthalimides/pharmacology , Structure-Activity Relationship , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/pharmacology
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