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1.
Drug Des Devel Ther ; 18: 1531-1546, 2024.
Article En | MEDLINE | ID: mdl-38737331

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.


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
2.
Bioorg Med Chem ; 106: 117753, 2024 May 15.
Article En | MEDLINE | ID: mdl-38749342

The expression of prostate-specific membrane antigen (PSMA) in prostate cancer is 100-1000 times higher than that in normal tissues, and it has shown great advantages in the diagnosis and treatment of prostate cancer. The combination of PSMA and PET imaging technology based on the principle of metabolic imaging can achieve high sensitivity and high specificity for diagnosis. Due to its suitable half-life (109 min) and good positron abundance (97%), as well as its cyclotron accelerated generation, 18F has the potential to be commercialize, which has attracted much attention. In this article, we synthesized a series of fluorosulfate PET tracers targeting PSMA. All four analogues have shown high affinity to PSMA (IC50 = 1.85-5.15 nM). After the radioisotope exchange labeling, [18F]L9 and [18F]L10 have PSMA specific cellular uptake (0.65 ± 0.04% AD and 1.19 ± 0.03% AD) and effectively accumulated in 22Rv1 xenograft mice model. This study demonstrates that PSMA-1007-based PSMA-targeted aryl [18F]fluorosulfate novel tracers have the potential for PET imaging in tumor tissues.


Antigens, Surface , Drug Design , Fluorine Radioisotopes , Positron-Emission Tomography , Radiopharmaceuticals , Animals , Humans , Male , Fluorine Radioisotopes/chemistry , Mice , Antigens, Surface/metabolism , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/chemistry , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/metabolism , Glutamate Carboxypeptidase II/metabolism , Molecular Structure , Cell Line, Tumor , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/metabolism , Structure-Activity Relationship
3.
Bioorg Chem ; 147: 107422, 2024 Jun.
Article En | MEDLINE | ID: mdl-38705106

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.


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
4.
Bioorg Chem ; 147: 107390, 2024 Jun.
Article En | MEDLINE | ID: mdl-38691904

Mobocertinib, as a structural analog of the third generation TKI Osimertinib, can selectively act on the EGFRex20 mutation. We have structurally modified Mobocertinib to obtain new EGFR inhibitors. In this paper, we chose Mobocertinib as a lead compound for structural modification to investigate the effect of Mobocertinib derivatives on EGFRT790M mutation. We designed and synthesized 63 Mobocertinib derivatives by structural modification using the structural similarity strategy and the bioelectronic isoarrangement principle. Then, we evaluated the in vitro antitumor activity of the 63 Mobocertinib derivatives and found that the IC50 of compound H-13 against EGFRL858R/T790M mutated H1975 cells was 3.91 µM, and in further kinase activity evaluation, the IC50 of H-13 against EGFRL858R/T790M kinase was 395.2 nM. In addition, the preferred compound H-13 was able to promote apoptosis of H1975 tumor cells and block the proliferation of H1975 cells in the G0/G1 phase; meanwhile, it was able to significantly inhibit the migratory ability of H1975 tumor cells and inhibit the growth of H1975 cells in a time-concentration-dependent manner. In the in vivo anti-tumor activity study, the preferred compound H-13 had no obvious toxicity to normal mice, and the tumor inhibition effect on H1975 cell-loaded nude mice was close to that of Mobocertinib. Finally, molecular dynamics simulations showed that the binding energy between compound H-13 and 3IKA protein was calculated to be -162.417 ± 14.559 kJ/mol. In summary, the preferred compound H-13 can be a potential third-generation EGFR inhibitor.


Antineoplastic Agents , Apoptosis , Cell Proliferation , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , ErbB Receptors , Protein Kinase Inhibitors , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Cell Proliferation/drug effects , Structure-Activity Relationship , Molecular Structure , Animals , Apoptosis/drug effects , Mice , Mice, Nude , Cell Line, Tumor , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism
5.
ACS Appl Bio Mater ; 7(5): 3306-3315, 2024 May 20.
Article En | MEDLINE | ID: mdl-38634490

Photodynamic therapy (PDT) and ferroptosis show significant potential in tumor treatment. However, their therapeutic efficacy is often hindered by the oxygen-deficient tumor microenvironment and the challenges associated with efficient intracellular drug delivery into tumor cells. Toward this end, this work synthesized perfluorocarbon (PFC)-modified Pluronic F127 (PFC-F127), and then exploits it as a carrier for codelivery of photosensitizer Chlorin e6 (Ce6) and the ferroptosis promoter sorafenib (Sor), yielding an oxygen self-supplying nanoplatform denoted as Ce6-Sor@PFC-F127. The PFCs on the surface of the micelle play a crucial role in efficiently solubilizing and delivering oxygen as well as increasing the hydrophobicity of the micelle surface, giving rise to enhanced endocytosis by cancer cells. The incorporation of an oxygen-carrying moiety into the micelles enhances the therapeutic impact of PDT and ferroptosis, leading to amplified endocytosis and cytotoxicity of tumor cells. Hypotonic saline technology was developed to enhance the cargo encapsulation efficiency. Notably, in a murine tumor model, Ce6-Sor@PFC-F127 effectively inhibited tumor growth through the combined use of oxygen-enhanced PDT and ferroptosis. Taken together, this work underscores the promising potential of Ce6-Sor@PFC-F127 as a multifunctional therapeutic nanoplatform for the codelivery of multiple cargos such as oxygen, photosensitizers, and ferroptosis inducers.


Antineoplastic Agents , Chlorophyllides , Drug Screening Assays, Antitumor , Ferroptosis , Fluorocarbons , Micelles , Oxygen , Photochemotherapy , Photosensitizing Agents , Ferroptosis/drug effects , Fluorocarbons/chemistry , Fluorocarbons/pharmacology , Animals , Mice , Photosensitizing Agents/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemical synthesis , Humans , Oxygen/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Materials Testing , Particle Size , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Biocompatible Materials/chemical synthesis , Porphyrins/chemistry , Porphyrins/pharmacology , Cell Survival/drug effects , Cell Proliferation/drug effects , Mice, Inbred BALB C , Sorafenib/chemistry , Sorafenib/pharmacology , Sorafenib/administration & dosage , Poloxamer/chemistry , Cell Line, Tumor , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism , Molecular Structure
6.
Eur J Med Chem ; 271: 116416, 2024 May 05.
Article En | MEDLINE | ID: mdl-38657480

Targeting polo-box domain (PBD) small molecule for polo-like kinase 1 (PLK1) inhibition is a viable alternative to target kinase domain (KD), which could avoid pan-selectivity and dose-limiting toxicity of ATP-competitive inhibitors. However, their efficacy in these settings is still low and inaccessible to clinical requirement. Herein, we utilized a structure-based high-throughput virtual screen to find novel chemical scaffold capable of inhibiting PLK1 via targeting PBD and identified an initial hit molecule compound 1a. Based on the lead compound 1a, a structural optimization approach was carried out and several series of derivatives with naphthalimide structural motif were synthesized. Compound 4Bb was identified as a new potent PLK1 inhibitor with a KD value of 0.29 µM. 4Bb could target PLK1 PBD to inhibit PLK1 activity and subsequently suppress the interaction of PLK1 with protein regulator of cytokinesis 1 (PRC1), finally leading to mitotic catastrophe in drug-resistant lung cancer cells. Furthermore, 4Bb could undergo nucleophilic substitution with the thiol group of glutathione (GSH) to disturb the redox homeostasis through exhausting GSH. By regulating cell cycle machinery and increasing cellular oxidative stress, 4Bb exhibited potent cytotoxicity to multiple cancer cells and drug-resistant cancer cells. Subcutaneous and oral administration of 4Bb could effectively inhibit the growth of drug-resistant tumors in vivo, doubling the survival time of tumor bearing mice without side effects in normal tissues. Thus, our study offers an orally-available, structurally-novel PLK1 inhibitor for drug-resistant lung cancer therapy.


Antineoplastic Agents , Cell Cycle Proteins , Cell Proliferation , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Lung Neoplasms , Naphthalimides , Polo-Like Kinase 1 , Protein Kinase Inhibitors , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins , Naphthalimides/chemistry , Naphthalimides/pharmacology , Naphthalimides/chemical synthesis , Humans , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Lung Neoplasms/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Animals , Structure-Activity Relationship , Mice , Molecular Structure , Drug Resistance, Neoplasm/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Cell Line, Tumor , Mice, Nude , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism
7.
Eur J Med Chem ; 271: 116433, 2024 May 05.
Article En | MEDLINE | ID: mdl-38678826

PD-1/PD-L1 pathway blockade is a promising immunotherapy for the treatment of cancer. In this manuscript, a series of triaryl compounds containing ester chains were designed and synthesized based on the pharmacophore studies of the lead BMS-1. After several SAR iterations, 22 showed the best biochemical activity binding to hPD-L1 with an IC50 of 1.21 nM in HTRF assay, and a KD value of 5.068 nM in SPR analysis. Cell-based experiments showed that 22 effectively promoted A549 cell death by restoring T-cell immune function. 22 showed significant in vivo antitumor activity in a 4T1 mouse model without obvious toxicity, with a TGI rate of 67.8 % (20 mg/kg, ip). Immunohistochemistry data indicated that 22 activates the immune activity in tumors. These results suggest that 22 is a promising compound for further development of PD-1/PD-L1 inhibitor for cancer therapy.


Antineoplastic Agents , B7-H1 Antigen , Esters , Programmed Cell Death 1 Receptor , Humans , Animals , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/metabolism , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/metabolism , Mice , Structure-Activity Relationship , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Molecular Structure , Esters/chemistry , Esters/pharmacology , Esters/chemical synthesis , Drug Screening Assays, Antitumor , Dose-Response Relationship, Drug , Cell Proliferation/drug effects , Mice, Inbred BALB C , Female , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Immune Checkpoint Inhibitors/pharmacology , Immune Checkpoint Inhibitors/chemistry , Immune Checkpoint Inhibitors/chemical synthesis
8.
Eur J Med Chem ; 271: 116415, 2024 May 05.
Article En | MEDLINE | ID: mdl-38643670

Fibroblast growth factor receptor (FGFR) is an attractive target for cancer therapy, but existing FGFR inhibitors appear to hardly meet the demand for clinical application. Herein, a number of irreversible covalent FGFR inhibitors were designed and synthesized by selecting several five- and six-membered azaheterocycles as parent scaffold with different substituents to take over the hydrophobic region in the active pocket of FGFR proteins. Among the resulting target compounds, III-30 showed the most potent effect on enzyme activity inhibition and anti-proliferative activity against the tested cancer cell lines. Significantly, III-30 could inhibit the enzyme activity by achieving irreversible covalent binding with FGFR1 and FGFR4 proteins. It could also regulate FGFR-mediated signaling pathway and mitochondrial apoptotic pathway to promote cancer cell apoptosis and inhibit cancer cell invasion and metastasis. Moreover, III-30 had a good metabolic stability and showed relatively potent anti-tumor activity in the MDA-MB-231 xenograft tumor mice model.


Antineoplastic Agents , Cell Proliferation , Drug Screening Assays, Antitumor , Protein Kinase Inhibitors , Humans , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Mice , Structure-Activity Relationship , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Molecular Structure , Cell Line, Tumor , Purines/pharmacology , Purines/chemistry , Purines/chemical synthesis , Drug Discovery , Apoptosis/drug effects , Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 1/metabolism , Dose-Response Relationship, Drug , Mice, Nude , Mice, Inbred BALB C , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism , Receptor, Fibroblast Growth Factor, Type 4/antagonists & inhibitors , Receptor, Fibroblast Growth Factor, Type 4/metabolism , Female
9.
Bioorg Chem ; 147: 107384, 2024 Jun.
Article En | MEDLINE | ID: mdl-38643568

Esophageal squamous cell carcinoma (ESCC) is a malignant tumor that is highly susceptible to metastasis, recurrence and resistance, and few therapeutic targets have been identified and proven effective. Herein, we demonstrated for the first time that Rap1b can positively regulate ESCC cell stemness, as well as designed and synthesized a novel class of Pt(IV) complexes that can effectively inhibit Raplb. In vitro biological studies showed that complex-1 exhibited stronger cytotoxicity than cisplatin and oxaliplatin against a variety of ESCC cells, and effectively reversed cisplatin-induced resistance of TE6 cells by increasing cellular accumulation of platinum and inhibiting cancer cell stemness. Significantly, complex-1 also exhibited strong ability to reversal cisplatin-induced cancer cell resistance and inhibit tumor growth in TE6/cDDP xenograft mice models, with a tumor growth inhibition rate of 73.3 % at 13 mg/kg and did not show significant systemic toxicity. Overall, Rap1b is a promising target to be developed as an effective treatment for ESCC. Complex-1, as the first Pt(IV) complex that can strongly inhibit Rap1b, is also worthy of further in-depth study.


Antineoplastic Agents , Cell Proliferation , Cisplatin , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Cisplatin/pharmacology , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/pathology , Esophageal Squamous Cell Carcinoma/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/pathology , Animals , Drug Resistance, Neoplasm/drug effects , Mice , Cell Proliferation/drug effects , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/pathology , Structure-Activity Relationship , Molecular Structure , Dose-Response Relationship, Drug , Ligands , Mice, Nude , rap GTP-Binding Proteins/metabolism , rap GTP-Binding Proteins/antagonists & inhibitors , Mice, Inbred BALB C , Organoplatinum Compounds/pharmacology , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/chemical synthesis , Cell Line, Tumor , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism , Coordination Complexes/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/chemical synthesis
10.
Drug Des Devel Ther ; 18: 1321-1338, 2024.
Article En | MEDLINE | ID: mdl-38681206

Purpose: Cinobufotalin injection has obvious curative effects on liver cancer patients with less toxicity and fewer side effects than other therapeutic approaches. However, the core ingredients and mechanism underlying these anti-liver cancer effects have not been fully clarified due to its complex composition. Methods: Multidimensional network analysis was used to screen the core ingredients, key targets and pathways underlying the therapeutic effects of cinobufotalin injection on liver cancer, and in vitro and in vivo experiments were performed to confirm the findings. Results: By construction of ingredient networks and integrated analysis, eight core ingredients and ten key targets were finally identified in cinobufotalin injection, and all of the core ingredients are tightly linked with the key targets, and these key targets are highly associated with the cell cycle-related pathways, supporting that both cinobufotalin injection and its core ingredients exert anti-liver cancer roles by blocking cell cycle-related pathways. Moreover, in vitro and in vivo experiments confirmed that either cinobufotalin injection or one of its core ingredients, cinobufagin, significantly inhibited cell proliferation, colony formation, cell cycle progression and xenograft tumor growth, and the key target molecules involved in the cell cycle pathway such as CDK1, CDK4, CCNB1, CHEK1 and CCNE1, exhibit consistent changes in expression after treatment with cinobufotalin injection or cinobufagin. Interestingly, some key targets CDK1, CDK4, PLK1, CHEK1, TTK were predicted to bind with multiple of core ingredients of cinobufotalin injection, and the affinity between one of the critical ingredients cinobufagin and key target CDK1 was further confirmed by SPR assay. Conclusion: Cinobufotalin injection was confirmed to includes eight core ingredients, and they play therapeutic effects in liver cancer by blocking cell cycle-related pathways, which provides important insights for the mechanism of cinobufotalin injection antagonizing liver cancer and the development of novel small molecule anti-cancer drugs.


Antineoplastic Agents , Bufanolides , Cell Proliferation , Liver Neoplasms , Bufanolides/pharmacology , Bufanolides/chemistry , Bufanolides/administration & dosage , Humans , Animals , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Liver Neoplasms/metabolism , Cell Proliferation/drug effects , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Drug Screening Assays, Antitumor , Liver Neoplasms, Experimental/drug therapy , Liver Neoplasms, Experimental/pathology , Liver Neoplasms, Experimental/metabolism , Mice, Inbred BALB C , Cell Cycle/drug effects , Mice, Nude , Dose-Response Relationship, Drug , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Neoplasms, Experimental/metabolism , Tumor Cells, Cultured , Structure-Activity Relationship , Molecular Structure , Injections
11.
ChemMedChem ; 19(9): e202300634, 2024 May 02.
Article En | MEDLINE | ID: mdl-38351876

The epithelial growth factor receptor (EGFR) signaling pathway has been proposed to benefit non-small cell lung cancer (NSCLC) treatment. In this manuscript, we investigated the modification of 2-aryl-4-aminoquinazoline, the classical backbone of the fourth-generation EGFR inhibitors, in addition to obtaining a series of novel 2-aryl-4-aminothienopyrimidine derivatives (A1~A45), we also gained further understanding of the modification of this framework. Derivatives were tested for cytotoxicity against cancer cell lines (cervical cancer cell line Hela, lung cancer cell lines A549, H1975, and PC-9, Ba/F3-EGFRDel19/T790M/C797S cells, and human normal hepatocytes LO2) as well as for the derivative's inhibitory activity against EGFRWT, EGFRL858R/T790M, and EGFRDel19/T790M/C797S kinase inhibitory activities. The results showed that most of the target compounds showed moderate to excellent activity against one or more cancer cell lines. Among them, the antitumor activity (IC50) of the most promising A9 against A549 and H1975 cell lines was 0.77±0.08 µM, 6.90±0.83 µM, respectively. At concentration of 10 µM, A9 can be employed as the fourth-generation of EGFR inhibitors with the ability to overcome the C797S drug resistance since it can suppress EGFRDel19/T790M/C797S cells and kinase by 98.90 % and 85.88 %, respectively. Moreover, the tumor-bearing nude mice experiment further shows that A9 can significantly inhibit the growth of tumor in vivo, with the tumor inhibition rate (TIR) of 55.92 %, which was equivalent to the positive group. After that, from the result of HE staining experiment and blood biochemical analysis experiment, A9 show low toxicity and good safety, which is worthy of further research and development.


Antineoplastic Agents , Cell Proliferation , Drug Screening Assays, Antitumor , ErbB Receptors , Mutation , Protein Kinase Inhibitors , Pyrimidines , Humans , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , ErbB Receptors/genetics , Pyrimidines/chemistry , Pyrimidines/pharmacology , Pyrimidines/chemical synthesis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/chemical synthesis , Structure-Activity Relationship , Cell Proliferation/drug effects , Animals , Mice , Molecular Structure , Cell Line, Tumor , Dose-Response Relationship, Drug , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Mice, Nude
12.
Int J Mol Sci ; 25(2)2024 Jan 09.
Article En | MEDLINE | ID: mdl-38255911

The chorioallantoic membrane (CAM) model, generated during avian development, can be used in cancer research as an alternative in vivo model to perform tumorigenesis in ovo due to advantages such as simplicity, low cost, rapid growth, and being naturally immunodeficient. The aim of this systematic review has been to compile and analyze all studies that use the CAM assay as a tumor induction model. For that, a systematic search was carried out in four different databases: PubMed, Scopus, Cochrane, and WOS. After eliminating duplicates and following the established inclusion and exclusion criteria, a total of 74 articles were included. Of these, 62% use the in ovo technique, 13% use the ex ovo technique, 9% study the formation of metastasis, and 16% induce tumors from patient biopsies. Regarding the methodology followed, the main species used is chicken (95%), although some studies use quail eggs (4%), and one article uses ostrich eggs. Therefore, the CAM assay is a revolutionary technique that allows a simple and effective way to induce tumors, test the effectiveness of treatments, carry out metastasis studies, perform biopsy grafts of patients, and carry out personalized medicine. However, unification of the methodology used is necessary.


Neoplasms, Experimental , Animals , Chick Embryo , Humans , Biological Assay , Chorioallantoic Membrane , Precision Medicine
13.
Mol Cancer Ther ; 23(2): 235-247, 2024 Feb 01.
Article En | MEDLINE | ID: mdl-37816248

E7130 is a novel anticancer agent created from total synthetic study of the natural compound norhalichondrin B. In addition to inhibiting microtubule dynamics, E7130 also ameliorates tumor-promoting aspects of the tumor microenvironment (TME) by suppressing cancer-associated fibroblasts (CAF) and promoting remodeling of tumor vasculature. Here, we demonstrate TME amelioration by E7130 using multi-imaging modalities, including multiplexed mass cytometry [cytometry by time-of-flight (CyTOF)] analysis, multiplex IHC analysis, and MRI. Experimental solid tumors characterized by large numbers of CAFs in TME were treated with E7130. E7130 suppressed LAP-TGFß1 production, a precursor of TGFß1, in CAFs but not in cancer cells; an effect that was accompanied by a reduction of circulating TGFß1 in plasma. To our best knowledge, this is the first report to show a reduction of TGFß1 production in TME. Furthermore, multiplex IHC analysis revealed reduced cellularity and increased TUNEL-positive apoptotic cells in E7130-treated xenografts. Increased microvessel density (MVD) and collagen IV (Col IV), an extracellular matrix (ECM) component associated with endothelial cells, were also observed in the TME, and plasma Col IV levels were also increased by E7130 treatment. MRI revealed increased accumulation of a contrast agent in xenografts. Moreover, diffusion-weighted MRI after E7130 treatment indicated reduction of tumor cellularity and interstitial fluid pressure. Overall, our findings strongly support the mechanism of action that E7130 alters the TME in therapeutically beneficial ways. Importantly, from a translational perspective, our data demonstrated MRI as a noninvasive biomarker to detect TME amelioration by E7130, supported by consistent changes in plasma biomarkers.


Antimitotic Agents , Cancer-Associated Fibroblasts , Neoplasms, Experimental , Neoplasms , Animals , Humans , Cancer-Associated Fibroblasts/pathology , Vascular Remodeling , Tumor Microenvironment , Endothelial Cells/pathology , Neoplasms/drug therapy , Antimitotic Agents/pharmacology
14.
J Mol Biol ; 436(1): 168372, 2024 01 01.
Article En | MEDLINE | ID: mdl-37979908

Brca1 mouse models were first reported in the mid-1990's shortly after cloning the human gene. Since then, many mouse models with a range of mutations have been generated, some mimic patient mutations, others are designed to probe specific protein domains and functions. In this review, we discuss early and recent studies using engineered Brca1 mouse alleles, and their implications for understanding Brca1 protein function in the context of DNA repair, tumorigenesis, and anti-cancer therapeutics.


BRCA1 Protein , Neoplasms, Experimental , Animals , Humans , Mice , BRCA1 Protein/genetics , BRCA1 Protein/metabolism , DNA Repair , Mutation , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/genetics
15.
Cancer Immunol Immunother ; 72(11): 3851-3859, 2023 Nov.
Article En | MEDLINE | ID: mdl-37612405

Radiation therapy (RT) treats approximately half of all cancers and most brain cancers. RT is variably effective at inducing a dormant tumor state i.e. the time between RT and clinical recurrence of tumor growth. Interventions that significantly lengthen tumor dormancy would improve long-term outcomes. Inflammation can promote the escape of experimental tumors from metastatic dormancy in the lung. Previously we showed intracerebral B16F10 melanoma dormancy varied with RT dose; 20.5 Gy induced dormancy lasted ~ 2 to 4 weeks-sufficient time to study escape from dormancy. Tumors were followed over time using bioluminescence. Surprisingly, some tumors in endotoxin-treated mice exited from dormancy slower; a large fraction of the mice survived more than 1-year. A cohort of mice also experienced an accelerated exit from dormancy and increased mortality indicating there might be variation within the tumor or inflammatory microenvironment that leads to both an early deleterious effect and a longer-term protective effect of inflammation. Some of the melanin containing cells at the site of the original tumor were positive for senescent markers p16, p21 and ßGal. Changes in some cytokine/chemokine levels in blood were also detected. Follow-up studies are needed to identify cytokines/chemokines or other mechanisms that promote long-term dormancy after RT.


Brain Neoplasms , Melanoma , Neoplasms, Experimental , Humans , Animals , Mice , Melanoma/pathology , Neoplasms, Experimental/pathology , Brain Neoplasms/radiotherapy , Tumor Microenvironment
16.
J Biomed Opt ; 28(7): 076001, 2023 07.
Article En | MEDLINE | ID: mdl-37457627

Significance: Pancreatic cancer tumors are known to be avascular, but their neovascular capillaries are still chaotic leaky vessels. Capillary permeability could have significant value for therapy assessment, and its quantification might be possible with macroscopic imaging of indocyanine green (ICG) kinetics in tissue. Aim: The capacity of using standard fluorescence surgical systems for ICG kinetic imaging as a probe for capillary leakage was evaluated using a clinical surgical fluorescence imaging system, as interpreted through vascular permeability modeling. Approach: Xenograft pancreatic adenocarcinoma models were imaged in mice during bolus injection of ICG to capture the kinetics of uptake. Image analysis included ratiometric data, normalization, and match to theoretical modeling. Kinetic data were converted into the extraction fraction of the capillary leakage. Results: Pancreatic tumors were usually less fluorescent than the surrounding healthy tissues, but still the rate of tumor perfusion could be assessed to quantify capillary extraction. Model simulations showed that flow kinetics stabilized after about 1 min beyond the initial bolus injection and that the relative extraction fraction model estimates matched the experimental data of normalized uptake within the tissue. The kinetics in the time period of 1 to 2 min post-injection provided optimal differential data between AsPC1 and BxPC3 tumors, although high individual variation exists between tumors. Conclusions: ICG kinetic imaging during the initial leakage phase was diagnostic for quantitative vascular permeability within pancreatic tumors. Methods for autogain correction and normalized model-based interpretation allowed for quantification of extraction fraction and difference identification between tumor types in early timepoints.


Adenocarcinoma , Neoplasms, Experimental , Pancreatic Neoplasms , Humans , Animals , Mice , Indocyanine Green , Capillary Permeability , Adenocarcinoma/diagnostic imaging , Pancreatic Neoplasms/diagnostic imaging , Disease Models, Animal , Optical Imaging/methods , Pancreatic Neoplasms
17.
J Physiol Biochem ; 79(3): 669-682, 2023 Aug.
Article En | MEDLINE | ID: mdl-37147492

Current evidence finds that circulating exosomal lncRNA focally amplified lncRNA on chromosome 1 (FAL1) promotes the progression of hepatocellular carcinoma (HCC). However, the underlying mechanism of serum extracellular vesicular FAL1 in HCC progression remains elusive. Here, we extracted extracellular vesicles (EVs) from serum samples of HCC patients and healthy volunteers, and found that FAL1 was highly enriched in the serum EVs of HCC patients. Then, macrophages were treated with EVs alone or together with small interfering RNA against FAL1 (si-FAL1). The data indicated that FAL1-enriched EVs induced macrophage M2 polarization, while silencing FAL1 in macrophages antagonized the role of EVs. Moreover, HepG2 cells were co-cultured with the conditioned macrophages, and co-culturing with EVs-incubated macrophages promoted HepG2 cell proliferation, invasion, cell cycle progression, and colony formation, and inhibited cell apoptosis and sorafenib sensitivity, while interfering FAL1 in macrophages reversed these effects. Consistently, ectopic expression of FAL1 in macrophages also induced macrophage M2 polarization, and co-culture of FAL1-overexpressing macrophages with HepG2 cells facilitated the malignant progression of HepG2 cells. Furthermore, co-culturing HepG2 cells with EVs-incubated macrophages activated the Wnt/ß-catenin signaling pathway, and treatment with a Wnt/ß-catenin pathway inhibitor IWP-2 partially neutralized the effect of EVs-incubated macrophages on HepG2 cell malignant behaviors. Additionally, FAL1 enriched EVs-incubated macrophages markedly increased mouse xenograft tumor growth. In conclusion, extracellular vesicular lncRNA FAL1 promotes macrophage M2 polarization and further activates the Wnt/ß-catenin signaling pathway in HCC cells, thus promoting HCC progression.


Carcinoma, Hepatocellular , Liver Neoplasms , Macrophage Activation , RNA, Long Noncoding , RNA, Long Noncoding/genetics , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/pathology , Cell Proliferation , Extracellular Vesicles , Humans , Hep G2 Cells , Wnt Signaling Pathway , Male , Female , Adult , Middle Aged , Animals , Mice , Mice, Inbred BALB C , Neoplasms, Experimental
18.
Cancer Med ; 12(12): 13573-13585, 2023 06.
Article En | MEDLINE | ID: mdl-37199371

OBJECTIVE: In order to ensure the stable transcription of target genes, we constructed a eukaryotic high expression vector carrying an immune-check inhibitor PD-1v and a variety of cytokines, and studied their effects on activating immune response to inhibit tumor growth. METHODS: A novel eukaryotic expression plasmid vector named pT7AMPCE containing T7RNA polymerase, T7 promoter, internal ribosome entry site (IRES), and poly A tailing signal was constructed by T4 DNA ligase, on which homologous recombination was used to clone and construct the vector carrying PD-1v, IL-2/15, IL-12, GM-CSF, and GFP. In vitro transfection of CT26 cells was performed, and the protein expression of PD-1v, IL-12 and GM-CSF was detected by Western blot and ELISA after 48 h. Mice were subcutaneously inoculated with CT26-IRFP tumor cells in the rib abdomen, and the tumor tissues were injected with PD-1v, IL-2/15, IL-12, and GM-CSF recombinant plasmids for treatment during the experimental period. The efficacy of the treatment was evaluated by assay tumor size and survival time of tumor-bearing mice during the experiment. Expression levels of IFN-γ, TNF, IL-4, IL-2, and IL-5 in mouse blood were measured using the CBA method. Tumor tissues were extracted and immune cell infiltration in tumor tissues was detected by HE staining and the IHC method. RESULTS: The recombinant plasmids carrying PD-1v, IL-2/15, IL-12, and GM-CSF were successfully constructed, and the Western blot and ELISA results showed that PD-1v, IL-12, and GM-CSF were expressed in the supernatant of CT26 cells 48 h after in vitro cell transfection. The combined application of PD-1v, IL-2/15, IL-12, and GM-CSF recombinant plasmids significantly inhibited tumor growth in mice, and the tumor growth rate was significantly lower than that in the blank control group and GFP plasmid control group (p < 0.05). Cytometric bead array data suggested that the combination of PD-1v and various cytokines can effectively activate immune cells. HE and IHC analysis revealed plenty of immune cell infiltrates in the tumor tissue, and a large proportion of tumor cells showed the necrotic phenotype in the combination treatment group. CONCLUSION: The combination of immune check blockade and multiple cytokine therapy can significantly activate the body's immune response and inhibit tumor growth.


Gene Targeting , Genetic Vectors , Granulocyte-Macrophage Colony-Stimulating Factor , Immunity , Interleukin-12 , Neoplasms , Programmed Cell Death 1 Receptor , Programmed Cell Death 1 Receptor/genetics , Animals , Mice , Promoter Regions, Genetic , DNA-Directed RNA Polymerases/genetics , Viral Proteins/genetics , Interleukin-12/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Female , Mice, Inbred BALB C , Neoplasms, Experimental/immunology , Neoplasms, Experimental/therapy , Neoplasms/immunology , Neoplasms/therapy , Transfection , Immunity/genetics , Gene Targeting/methods , Green Fluorescent Proteins
19.
Int Immunol ; 35(8): 387-400, 2023 08 07.
Article En | MEDLINE | ID: mdl-37202206

The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.


CD4-Positive T-Lymphocytes , Interleukin-12 , Neoplasms, Experimental , Tumor Microenvironment , Animals , Mice , CD4-Positive T-Lymphocytes/immunology , Interleukin-12/immunology , T-Cell Exhaustion , Lymphocytes, Tumor-Infiltrating/immunology , Mice, Inbred BALB C , Neoplasms, Experimental/immunology , Memory T Cells/immunology , Granzymes , Perforin
20.
J Mol Biol ; 435(13): 168096, 2023 07 01.
Article En | MEDLINE | ID: mdl-37086948

Human papilloma virus (HPV) infections are associated with almost all cervical cancers and to a lower extend also with anogenital or oropharyngeal cancers. HPV proteins expressed in HPV-associated tumors are attractive antigens for cancer vaccination strategies as self-tolerance, which is associated with most endogenous tumor-associated antigens, does not need to be overcome. In this study, we generated a live attenuated cancer vaccine based on the chimeric vesicular stomatitis virus VSV-GP, which has previously proven to be a potent vaccine vector and oncolytic virus. Genes at an earlier position in the genome more to the 3' end are expressed stronger compared to genes located further downstream. By inserting an HPV16-derived antigen cassette consisting of E2, E6 and E7 into VSV-GP either at first (HPVp1) or fifth (HPVp5) position in VSV-GP's genome we aimed to analyze the effect of vaccine antigen position and consequently expression level on viral fitness, immunogenicity, and anti-tumoral efficacy in a syngeneic mouse tumor model. HPVp1 expressed higher amounts of HPV antigens compared to HPVp5 in vitro but had a slightly delayed replication kinetic which overall translated into increased HPV-specific T cell responses upon vaccination of mice. Immunization with both vectors protected mice in prophylactic and in therapeutic TC-1 tumor models with HPVp1 being more effective in the prophylactic setting. Taken together, VSV-GP is a promising candidate as therapeutic HPV vaccine and first position of the vaccine antigen in a VSV-derived vector seems to be superior to fifth position.


Neoplasms , Papillomavirus Infections , Papillomavirus Vaccines , Vesiculovirus , Animals , Humans , Mice , Human Papillomavirus Viruses , Mice, Inbred C57BL , Neoplasms/therapy , Neoplasms/virology , Papillomavirus Infections/therapy , Papillomavirus Vaccines/genetics , Papillomavirus Vaccines/therapeutic use , Vaccines, Attenuated , Neoplasms, Experimental
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