Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
Add more filters










Database
Publication year range
1.
Neoplasma ; 68(5): 1033-1042, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34427098

ABSTRACT

It has been reported that cyclin-dependent kinase like 3 (CDKL3) plays a crucial role in cell proliferation and migration in several cancers. However, the function of CDKL3 in triple-negative breast cancer (TNBC) is still unclear. In the present study, immunohistochemistry (IHC) was conducted to detect the CDKL3 expression. CCK-8, flow cytometry, Transwell assays, and mice xenograft models, were performed to explore the roles of CDKL3 on the proliferation and migration of TNBC in vitro and in vivo. Besides, protein chip analysis was used to screen the potential pathways, which was further confirmed by promoter activity assay, western blotting, and CCK-8 assay. Our findings reveal a high expression of CDKL3 in TNBC tissues, which is closely related to a poor prognosis of patients with TNBC. In TNBC cells, CDKL3 knockdown inhibits cell proliferation and migration, whereas CDKL3 overexpression has exactly the opposite effect. Consistently, CDKL3 knockdown induces cell apoptosis in vitro but suppresses tumor growth in vivo. Furthermore, CDKL3 knockdown increases p53 expression and reduces cell viability, and these effects are significantly weakened by the p53 inhibitor, PFT-α. In conclusion, the current study highlights that CDKL3 promotes TNBC progressions via regulating the p53 signaling pathway, suggesting that CDKL3 is a novel therapeutic target for TNBC treatment.


Subject(s)
Protein Serine-Threonine Kinases/metabolism , Triple Negative Breast Neoplasms , Animals , Cell Line, Tumor , Cell Proliferation , Gene Expression Regulation, Neoplastic , Humans , Mice , Protein Serine-Threonine Kinases/genetics , Signal Transduction , Triple Negative Breast Neoplasms/genetics , Tumor Suppressor Protein p53/genetics
2.
Pathol Oncol Res ; 27: 580800, 2021.
Article in English | MEDLINE | ID: mdl-34257526

ABSTRACT

Background: Cholinesterase (CHE) is a routine serum biomarker in gastric cancer (GC). However, little research has been done on its clinical value in advanced GC. In addition, it is not clear whether it can be used as biomarker for the response and prognosis of advanced GC patients. Methods: Between Jan. 2013 and Dec. 2016, a total of 150 patients with advanced GC treated with first-line chemotherapy were admitted to Changzhou Tumor Hospital Affiliated to Soochow University. We retrospectively identified serum CHE level on the day before chemotherapy and at the end of chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between serum CHE levels and progression-free survival (PFS) and overall survival (OS). Results: A total of 150 advanced GC patients were included and divided into serum level ≥5,000 IU/L and serum level <5,000 IU/L. CHE level lower than 5,000 IU/L was associated with poorer PFS (HR, 1.60; 95% CI, 1.141-2.243; p = 0.006), poorer OS (HR, 1.76; 95% CI, 1.228-2.515; p = 0.002) and trend of poorer response (HR, 0.56; 95% CI, 0.272-1.129; p = 0.104). In univariate and multivariate logistic regression analysis, only liver metastasis and PS score were significantly associated with objective response (p < 0.05). The medium PFS was 8.0 months in patients with post-treatment CHE increased vs. 3.8 months in patients with CHE decreased after chemotherapy (HR, 1.82; 95% CI 1.28-2.57; p = 0.0002). The medium OS was 13.1 months in patients with increased post-treatment CHE vs. 8.1 months in patients with decreased post-treatment CHE (HR, 1.87; 95% CI 1.29-2.71; p = 0.0002). Conclusion: Advanced GC with CHE levels below 5,000 IU/L was significantly associated with poor PFS and OS. The results suggested that CHE analysis before chemotherapy was a promising prognostic marker for advanced GC.


Subject(s)
Cholinesterases/blood , Stomach Neoplasms/enzymology , Aged , Biomarkers, Tumor/blood , Female , Humans , Male , Middle Aged , Prognosis , Progression-Free Survival , Retrospective Studies , Stomach Neoplasms/drug therapy , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Rate , Treatment Outcome
3.
J Med Chem ; 56(17): 7110-9, 2013 Sep 12.
Article in English | MEDLINE | ID: mdl-23981033

ABSTRACT

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development.


Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Lactams/pharmacology , Animals , Area Under Curve , Lactams/chemistry , Magnetic Resonance Spectroscopy
4.
Bioorg Med Chem Lett ; 23(16): 4571-8, 2013 Aug 15.
Article in English | MEDLINE | ID: mdl-23831135

ABSTRACT

Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.


Subject(s)
Enzyme Activators/chemistry , Glucokinase/metabolism , Pyrimidinones/chemical synthesis , Allosteric Regulation , Amino Acid Motifs , Animals , Binding Sites , Models, Molecular , Pyrimidinones/chemistry , Rats
5.
Bioorg Med Chem Lett ; 22(23): 7100-5, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23089526

ABSTRACT

Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N-(5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy.


Subject(s)
Drug Design , Glucokinase/chemistry , Hypoglycemic Agents/chemical synthesis , Indazoles/chemistry , Pyrazines/chemical synthesis , Pyrazoles/chemistry , Pyridines/chemistry , Administration, Oral , Animals , Cell Line, Tumor , Diabetes Mellitus, Type 2/drug therapy , Glucokinase/metabolism , Glucose Tolerance Test , Half-Life , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Indazoles/chemical synthesis , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Insulin/metabolism , Kinetics , Protein Binding , Pyrazines/pharmacokinetics , Pyrazines/therapeutic use , Pyrazoles/pharmacokinetics , Pyrazoles/therapeutic use , Pyridines/pharmacokinetics , Pyridines/therapeutic use , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
6.
J Med Chem ; 54(8): 2952-60, 2011 Apr 28.
Article in English | MEDLINE | ID: mdl-21449606

ABSTRACT

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Drug Discovery , Sodium-Glucose Transporter 2 Inhibitors , Animals , Area Under Curve , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Crystallography, X-Ray , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Rats
7.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 17(6): 1538-40, 2009 Dec.
Article in Chinese | MEDLINE | ID: mdl-20030942

ABSTRACT

To investigate the effect of donor lymphocyte infusion (DLI) by intra-bone marrow (IBM) routes on the incidence of graft-versus-host disease(GVHD), level of IL-4 and IFN-gamma after allogeneic peripheral hematopoietic stem cell transplantation (allo-PBSCT). Female C57BL/6 mice as recipients received total body irradiation (TBI) on day 0, followed by injection of peripheral hematopoietic stem cells from mobilized donor of male BALB/c with the granulocyte-colony stimulating factor (rhG-CSF), and DLI was performed via ether IV or IBM routes. The severity of GVHD was compared in recipients received allogeneic IBM-DLI with those mice received IV-DLI; at 14 days after DLI, the levels of IL-4 and interferon (IFN)-gamma were tested by ELISA. The results showed that as compared with IV-DLI group the frequency and severity of GVHD were reduced in IBM-DLI (p < 0.01); the level of IL-4 significantly increased, while the level of IFN-gamma decreased in group IV-DLI (p < 0.01). It is concluded that IBM-DLI declines the incidence and severity of GVHD after allo-PBSCT.


Subject(s)
Graft vs Host Disease/prevention & control , Interferon-gamma/blood , Interleukin-4/blood , Lymphocyte Transfusion/methods , Animals , Bone Marrow/physiology , Female , Hematopoietic Stem Cells/physiology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
8.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 15(5): 1009-12, 2007 Oct.
Article in Chinese | MEDLINE | ID: mdl-17956680

ABSTRACT

This study was aimed to explore whether the graft-versus-host disease (GVHD) could be alleviated by intra-bone marrow (IBM) infusion of allogeneic hematopoietic stem cells. Female C57BL/6 mice as recipients received total body irradiation (TBI) 4 Gy on day 0, followed by injection of peripheral hematopoietic stem cells (1 x 10(7)) from mobilized male BALB/c with granulocyte-colony stimulating factor (rhG-CSF), and cyclophosphamide (200 mg/kg) was injected intraperitoneally two days later. The results showed that the incidence and severity of GVHD were more low and alleviative in group IBM-PBSCT than that in group TV-PBSCT (p < 0.05). Y chromosome of donor mice could be detected in the bone marrow of recipient mice. It is concluded that the method of intra-bone marrow infusion is superior to injection via the tail vein in the engraftment of hematopoietic stem cells in terms of stem cell homing while the frequency and severity of GVHD in allogeneic mice decrease.


Subject(s)
Graft vs Host Disease/prevention & control , Peripheral Blood Stem Cell Transplantation/adverse effects , Peripheral Blood Stem Cell Transplantation/methods , Animals , Cyclophosphamide/therapeutic use , Female , Granulocyte Colony-Stimulating Factor/therapeutic use , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Models, Animal , Recombinant Proteins , Whole-Body Irradiation
9.
J Org Chem ; 67(9): 3134-7, 2002 May 03.
Article in English | MEDLINE | ID: mdl-11975581

ABSTRACT

A synthetic approach to the hyperevolutin A acylated phloroglucinol ring system is described. Thus, intramolecular allene-nitrile oxide cycloaddition of 10 was used to construct the bicyclic framework and vicinal quaternary centers in cycloadduct 20 in the key bond-forming step. Treatment of 20 with Raney nickel and hydrogen gas produced primary enamine 21 which contains a nonenolizable beta,beta-tricarbonyl group in latent form.


Subject(s)
Biological Factors/chemical synthesis , Clusiaceae/chemistry , Plants, Medicinal/chemistry , Terpenes/chemical synthesis , Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Bridged Bicyclo Compounds , Catalysis , Crystallography, X-Ray , Cyclization , Magnetic Resonance Spectroscopy , Molecular Structure , Phloroglucinol/analogs & derivatives , Stereoisomerism
SELECTION OF CITATIONS
SEARCH DETAIL
...