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1.
Dalton Trans ; 53(8): 3675-3684, 2024 Feb 20.
Article in English | MEDLINE | ID: mdl-38293800

ABSTRACT

Coordination-driven self-assembly processes often produce remarkable structures. In particular, self-assembly processes mediated by chiral template units have provided research ideas for analyzing the formation of chiral macromolecules in living organisms. In this study, by regulating the proportion of reaction raw materials in the "one-pot" synthesis of lanthanide complexes, we constructed chiral template units with different coordination orientations. As a result, lanthanide chiral chains connected to different structures were obtained through the self-assembly process of coordination recognition. In particular, driven by coordination, chiral template units with codirectional coordination points (called cis configuration) coordinate solely with cis template units during the self-assembly process to obtain a one-dimensional (1D) chain R-1/S-1 with an "S"-shaped distribution. Moreover, chiral template units with reversed coordination sites (called trans configuration) and twisted chiral template units are connected solely to templates with the same configuration to form a 1D chain R-2/S-2 with an axial helix. A circular dichroism spectrum shows that R-1/S-1 and R-2/S-2 are two pairs of enantiomers. The controllable construction of these two differential 1D chains is of great significance for studying coordination recognition at the molecular level. To the best of our knowledge, this is the first study to construct a 1D lanthanide chain through the self-assembly process of coordination recognition. The assembly process of nucleotides to form a hierarchical structure is simulated. This work provides a vivid example of the controllable synthesis of lanthanide complexes with precise structures and offers a new perspective on the formation process of chiral macromolecules that simulates natural processes.

2.
J Med Biochem ; 42(4): 607-615, 2023 Oct 27.
Article in English | MEDLINE | ID: mdl-38084245

ABSTRACT

Background: To explore the difference and diagnostic value evaluation of serum tumor markers in different clinical stages of elderly non-small cell lung cancer (NSCLC) patients. Methods: Select 100 elderly NSCLC patients admitted to our hospital from June 2018 to June 2021, collect the general data, pathology data and imaging data of the patients, and the patients were divided into I-IV clinical stages according to the International Union Against Cancer (UICC) 8th edition lung cancer TNM staging standard. Detect the subjects' peripheral serum tumor markers, serum carcinoembryonic antigen (CEA), cytokeratin fragment 21-1 (CYFRA21-1), squamous cell carcinoma-associated antigen (SCCA), carbohydrate antigen 125 (CA125) and sugar Class antigen 199 (CA199). Compare the differences of serum CEA, CYFRA21-1, SCCA, CA125, CA199 levels in different clinical stages of elderly NSCLC patients, and the diagnostic value of the above indicators for elderly NSCLC patients was analyzed by receiver operating characteristic curve (ROC curve) and area under the curve (AUC).

3.
Expert Rev Hematol ; 16(12): 1135-1142, 2023.
Article in English | MEDLINE | ID: mdl-37883026

ABSTRACT

OBJECTIVE: Currently, immune checkpoint inhibitors (ICIs) therapy is one of the main methods of treatment in non-small cell lung cancer (NSCLC). This study aimed to explore the risk factors of VTE and evaluate the effect of ICIs on VTE in patients with NSCLC. RESEARCH DESIGN AND METHODS: We retrospectively studied patients with NSCLC who were divided into VTE group and without VTE (Non-VTE) group. We identified the risk factors of VTE in NSCLC patients and evaluated the effect of ICIs on VTE in NSCLC patients. RESULTS: We found that clinical stage III-IV (P = 0.015) and Khorana score (KS) ≥ 2 (P = 0.047) were independent risk factors for the occurrence of VTE in NSCLC, and treatment with ICIs reduced the risk of VTE occurrence (P = 0.028). There were no differences of survival rates in the 12-month (P = 0.449), 24-month (P = 0.412), or 36-month (P = 0.315) between the VTE and non-VTE groups. History of anti-angiogenic therapy (P = 0.033) and chronic obstructive pulmonary disease (COPD) (P = 0.046) were independent risk factors for VTE in NSCLC patients who were treated with ICIs. CONCLUSION: This study suggests that we should strengthen anticoagulant therapy when using ICIs for NSCLC patients with a history of anti-angiogenic therapy and COPD.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Pulmonary Disease, Chronic Obstructive , Venous Thromboembolism , Humans , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Immune Checkpoint Inhibitors/adverse effects , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/epidemiology , Retrospective Studies , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/drug therapy
4.
Sci Rep ; 12(1): 17201, 2022 10 13.
Article in English | MEDLINE | ID: mdl-36229645

ABSTRACT

Lung cancer is the leading cause of cancer-related death worldwide. MicroRNAs (miRNAs) in circulating small extracellular vesicles (sEVs) have been suggested to be potential biomarkers for cancer diagnosis. The present study was designed to explore whether plasma-derived sEV miRNAs could be utilized as diagnostic biomarkers for differentiating between early-stage small cell lung cancer (SCLC) and early-stage non-small cell lung cancer (NSCLC). We compared the miRNA profiles of plasma-derived sEVs from healthy individuals, patients with early-stage SCLC and patients with early-stage NSCLC. Next-generation sequencing was used to screen for differentially expressed miRNAs (DEMs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to predict the potential functions of these DEMs. Weighted gene coexpression network analysis (WGCNA) was used to identify the different pathology-related miRNA modules. We found that 22 DEMs were significantly different among healthy individuals, patients with early-stage SCLC, and patients with early-stage NSCLC. We selected six representative DEMs for validation by qRT‒PCR, which confirmed that miRNA-483-3p derived from plasma sEVs could be used as a potential biomarker for the diagnosis of early-stage SCLC, miRNA-152-3p and miRNA-1277-5p could be used for the diagnosis of early-stage NSCLC respectively.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating MicroRNA , Extracellular Vesicles , Lung Neoplasms , MicroRNAs , Small Cell Lung Carcinoma , Biomarkers, Tumor/genetics , Carcinoma, Non-Small-Cell Lung/diagnosis , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Extracellular Vesicles/genetics , Extracellular Vesicles/pathology , Gene Expression Profiling , Humans , Lung Neoplasms/diagnosis , Lung Neoplasms/genetics , Lung Neoplasms/pathology , MicroRNAs/genetics , Small Cell Lung Carcinoma/diagnosis , Small Cell Lung Carcinoma/genetics
5.
Ann Palliat Med ; 11(7): 2503-2509, 2022 Jul.
Article in English | MEDLINE | ID: mdl-35927783

ABSTRACT

BACKGROUND: For epidermal growth factor receptor-mutant (EGFR-mutant) advanced non-small cell lung cancer (NSCLC) patients, EGFR-tyrosine inhibitors such as gefitinib, erlotinib, and osimertinib, are recommended as the preferred first-line treatment. Unfortunately, relevant drug resistance is often inevitable and for first and second generation EGFR-tyrosine kinase inhibitors (TKIs), drug resistance most commonly (50-60% of cases) occurs at the secondary point mutation T790M. Second-line treatments may include administering the third generation of EGFR-TKIs, such as osimertinib and almonertinib. In a few relevant studies, rearrangement of the anaplastic lymphoma kinase (ALK) gene was detected in patients with T790M mutation after drug resistance to osimertinib re-occurred following administration as a second-line treatment. The studies concluded that ALK rearrangement is a rare but critical drug resistance mechanism for osimertinib. However, to date, it remains unclear whether almonertinib also triggers the same ALK rearrangement. The current case study is the first one detailing the detection of an ALK rearrangement after almonertinib resistance in advanced EGFR-mutant NSCLC, which contributes to the limited body of literature examining ALK rearrangement as a mechanism of resistance to EGFR-TKIs in advanced EGFR-mutant NSCLC. CASE DESCRIPTION: Herein, we present a 35-year-old female patient with EGFR-mutant advanced NSCLC in the last trimester of pregnancy. The patient was administered multiple treatments, including first-line icotinib and second-line almonertinib. According to the next-generation sequencing (NGS) assay after almonertinib resistance, the development of an EML4-ALK fusion mutation was considered to be a potential mechanism of almonertinib resistance. Subsequently, the patient received a combination of almonertinib and crizotinib, and at the last follow-up, the treatment showed a curative effect and then maintained a one-month stable disease. CONCLUSIONS: This case report suggests that ALK rearrangement may be a potential mechanism of almonertinib resistance. The combination of ALK TKI therapy and EGFR TKI may be a viable strategy for almonertinib-resistant NSCLC patients induced by ALK rearrangement.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Acrylamides , Adult , Anaplastic Lymphoma Kinase/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , Female , Humans , Indoles , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/pharmacology , Oncogene Proteins, Fusion/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines
6.
Bioorg Med Chem ; 27(1): 65-78, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30502115

ABSTRACT

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Herein, we reported a series of 2,4-bisanilinopyrimidines bearing 2,2,6,6-tetramethylpiperidine-N-oxyl with selective inhibition of Aurora A in either enzymatic assays or cellular phenotypic assays, and displaying more potent anti-proliferation compared with that of VX-680. The most potent compound 10a forms better interaction with Aurora A than Aurora B in molecular docking. Mechanistic studies revealed that 10a disrupt the spindle formation, block the cell cycle progression in the G2/M phase and induce apoptosis in HeLa cell. These results suggested that the produced series of compounds are potential anticancer agents for further development as selective Aurora A inhibitors.


Subject(s)
Aniline Compounds/pharmacology , Cyclic N-Oxides/pharmacology , Piperidines/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Aniline Compounds/chemical synthesis , Aniline Compounds/chemistry , Apoptosis/drug effects , Aurora Kinase A/chemistry , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclic N-Oxides/chemical synthesis , Cyclic N-Oxides/chemistry , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Molecular Docking Simulation , Piperidines/chemical synthesis , Piperidines/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Spindle Apparatus/drug effects
7.
Oncol Rep ; 40(5): 2944-2954, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30226581

ABSTRACT

In the present study, the therapeutic effects and the underlying molecular mechanisms of microRNA (miR)­145 were investigated in non­small cell lung cancer (NSCLC) cells. Reverse transcription­quantitative polymerase chain reaction (RT­qPCR) was performed to examine miR­145 expression. An MTT assay and flow cytometry were used to investigate cell proliferation and apoptosis, respectively. The protein expression of Bax, epidermal growth factor receptor (EGFR), phosphatidylinositol 3­kinase (PI3K) and phosphorylated­protein kinase B (AKT) was examined by western blot analysis. miR­145 expression was downregulated in patients with NSCLC who were treated with chemotherapy. The downregulation of miR­145 in A549 cells reduced lactate dehydrogenase (LDH) expression, apoptosis, caspase­3/-9 levels and Bax protein expression, while it increased cell proliferation. Upregulation of miR­145 in A459 cells increased LDH, apoptosis, caspase­3/-9 levels and Bax protein expression, while it inhibited cell proliferation. The EGFR/PI3K/AKT signaling pathway was suppressed by miR­145 upregulation in A549 cells and induced by miR­145 downregulation. The EGFR inhibitor suppressed the EGFR/PI3K/AKT signaling pathway and increased the anticancer effects of miR­145 upregulation in A549 cells. The PI3K inhibitor suppressed the PI3K/AKT signaling pathway and reversed the anticancer effects of miR­145 upregulation in A549 cells. In conclusion, the present study demonstrated that miR­145 regulates the EGFR/PI3K/AKT signaling pathway in patients with NSCLC.


Subject(s)
Carcinoma, Non-Small-Cell Lung/genetics , MicroRNAs/genetics , Neoplasm Proteins/genetics , A549 Cells , Apoptosis/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Movement/genetics , Cell Proliferation/genetics , ErbB Receptors/genetics , Gene Expression Regulation, Neoplastic , Humans , Oncogene Protein v-akt/genetics , Phosphatidylinositol 3-Kinases/genetics , Signal Transduction/genetics
8.
Oncol Rep ; 39(3): 1227-1234, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29344640

ABSTRACT

The present study determined the anticancer activity and its mechanism of microRNA­133b on cell proliferation of cisplatin-induced non-small cell lung cancer cells. The expression of microRNA-133b cisplatin­induced non-small cell lung cancer (NSCLC) tissue was lower than that of para-carcinoma tissue in patients. Overall survival of higher expression in cisplatin-induced NSCLC patients was higher than that of lower expression in cisplatin­induced NSCLC patients. Over-regulation of microRNA-133b inhibited cell proliferation and LDH activity, induced apoptosis and caspase-3 activity, suppressed the protein expression of EGFR, PI3K, p-Akt, p-JAK2 and p-STAT3, decreased cyclin D1 and increased Bax protein expression in cisplatin­induced A549 cells. EGFR inhibitor (lapatinib) suppressed EGFR protein expression, inhibited cell proliferation and LDH activity, and induced apoptosis and caspase-3 activity in cisplatin-induced A549 cells by over-regulation of microRNA-133b. When EGFR protein expression was suppressed, PI3K, p-Akt, p-JAK2 and p-STAT3, decreased cyclin D1 and increased Bax protein expression in cisplatin-induced A549 cells by over-regulation of microRNA-133b. Altogether, our results indicated that over-regulation of microRNA-133b inhibits cell proliferation of cisplatin-induced NSCLC by PI3K/Akt and JAK2/STAT3 signaling pathway by targeting EGFR.


Subject(s)
Carcinoma, Non-Small-Cell Lung/pathology , Cell Proliferation/drug effects , Cisplatin/pharmacology , Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms/pathology , MicroRNAs/genetics , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , STAT3 Transcription Factor/genetics , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Tumor Cells, Cultured
9.
Eur J Med Chem ; 95: 174-84, 2015 May 05.
Article in English | MEDLINE | ID: mdl-25812967

ABSTRACT

The Aurora kinases are a family of serine/threonine kinases that interact with components of the mitotic apparatus and serve as potential therapeutic targets in oncology. Here we synthesized 15 2,4-diaminopyrimidines and evaluated their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects. These compounds generally exhibited more potent cytotoxicity against tumor cell lines compared with the VX-680 control, especially compound 11c, which showed the highest cytotoxicities, with IC50 values of 0.5-4.0 µM. Compound 11c had more than 35-fold more selectivity for Aurora A over Aurora B, and molecular docking analysis indicated that compound 11c form better interaction with Aurora A both from the perspective of structure and energy. Furthermore, compound 11c induced G2/M cell cycle arrest in HeLa cells. This series of compounds has the potential for further development as selective Aurora A inhibitors for anticancer activity.


Subject(s)
Aurora Kinase A/antagonists & inhibitors , Aurora Kinase B/antagonists & inhibitors , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemistry , Cell Cycle/drug effects , Cell Proliferation/drug effects , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , HeLa Cells , Humans , Immunoblotting , Molecular Docking Simulation
10.
Bioorg Med Chem Lett ; 23(24): 6650-5, 2013 Dec 15.
Article in English | MEDLINE | ID: mdl-24231363

ABSTRACT

We found that the deoxypodophyllotoxin derivative, 2,6-dimethoxy-4-(6-oxo-(5R,5aR,6,8,8aR,9-hexahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-5-yl)phenyl ((R)-1-amino-4-(methylthio)-1-oxobutan-2-yl)carbamate (DPMA), exhibited superior cytotoxicity compared with etoposide. In this study, we investigated the mechanism of action of DPMA. DPMA exhibited anti-proliferative activity and induced apoptosis in A549 cells in a dose- and time-dependant manner. DPMA inhibited microtubule formation and induced expression of Bax, cleaved caspase-3, p53 and ROS, and inhibited Bcl-2 expression. DPMA also affected cyclinB1, cdc2 and p-cdc2 expression, inducing cell cycle arrest. DPMA also inhibited tube formation of VEGF-induced human umbilical vein endothelial cells. These studies demonstrate that DPMA inhibits p53/cdc2/Bax signaling, thereby inhibiting cell growth/angiogenesis and inducing apoptosis.


Subject(s)
Adenosine/analogs & derivatives , Apoptosis/drug effects , Neovascularization, Physiologic/drug effects , Podophyllotoxin/analogs & derivatives , Adenosine/chemistry , Adenosine/pharmacology , CDC2 Protein Kinase/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Drugs, Chinese Herbal , Human Umbilical Vein Endothelial Cells , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Podophyllotoxin/chemistry , Podophyllotoxin/pharmacology , Signal Transduction/drug effects , Tumor Suppressor Protein p53/metabolism , Vascular Endothelial Growth Factor A/pharmacology , bcl-2-Associated X Protein/metabolism
11.
Eur J Med Chem ; 70: 59-67, 2013.
Article in English | MEDLINE | ID: mdl-24140948

ABSTRACT

A series of carbamate derivatives of 4'-demethylepipodophyllotoxin have been synthesized, and their cytotoxicities against several human cancer cell lines, including HeLa, A549, HCT-8, and HL-60 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4ß-4'-Demethylepipodophyllotoxin 1-(4-nitrophenyl) piperazinyl carbamate (19) was found to be the most potent compound of those synthesized in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of Bax, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Carbamates/pharmacology , DNA/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Carbamates/chemical synthesis , Carbamates/chemistry , Cattle , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HL-60 Cells , HeLa Cells , Humans , Molecular Structure , Structure-Activity Relationship
12.
Bioorg Med Chem ; 21(22): 6948-55, 2013 Nov 15.
Article in English | MEDLINE | ID: mdl-24095019

ABSTRACT

A series of 4ß-amino-4'-O-demethyl-4-deoxypodophyllotoxin derivatives were synthesized, and their cytotoxicities against several human cancer cell lines, including HepG2, A549, HeLa and HCT-8 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4ß-N-(4-Nitrophenyl piperazinyl)-4'-O-demethyl-4-deoxypodophyllotoxin (11) was found to be the most potent synthesized compound in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of cdc2, cyclin B1, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.


Subject(s)
Antineoplastic Agents/chemical synthesis , DNA/metabolism , Piperazines/chemical synthesis , Podophyllotoxin/analogs & derivatives , Animals , Antineoplastic Agents/toxicity , Apoptosis/drug effects , CDC2 Protein Kinase/metabolism , Caspase 3/metabolism , Cattle , Cell Line, Tumor , Cyclin B1/metabolism , Drugs, Chinese Herbal , G2 Phase Cell Cycle Checkpoints/drug effects , HeLa Cells , Hep G2 Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , Microtubules/chemistry , Microtubules/metabolism , Piperazines/metabolism , Piperazines/toxicity , Podophyllotoxin/chemical synthesis , Podophyllotoxin/chemistry , Podophyllotoxin/metabolism , Podophyllotoxin/toxicity , Tubulin Modulators/chemical synthesis , Tubulin Modulators/metabolism , Tubulin Modulators/toxicity , Tumor Suppressor Protein p53/metabolism
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