scholarly journals Expression of PAFR as Part of a Prosurvival Response to Chemotherapy: A Novel Target for Combination Therapy in Melanoma

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Ana Claudia Onuchic ◽  
Camila M. L. Machado ◽  
Renata F. Saito ◽  
Francisco J. Rios ◽  
Sônia Jancar ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Platelet Activating Factor ◽  
Tumour Microenvironment ◽  
Melanoma Cells ◽  
Signalling Pathways ◽  
Control Group ◽  
Promising Target ◽  
Response To Chemotherapy ◽  
Novel Target

Melanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cellsin vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas.

scholarly journals CD1d expression in glioblastoma is a promising target for NKT cell-based cancer immunotherapy

2020 ◽  
Author(s):  
Ayaka Hara ◽  
Ryo Koyama-Nasu ◽  
Mariko Takami ◽  
Takahide Toyoda ◽  
Takahiro Aoki ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Inkt Cell ◽  
Glioblastoma Cells ◽  
Inkt Cells ◽  
Nkt Cell ◽  
Promising Target ◽  
Differentiating Agent ◽  
Novel Target ◽  
Orthotopic Xenografts

Abstract Glioblastoma is the most common and aggressive type of brain tumor with high recurrence and fatality rates. Although various therapeutic strategies have been explored, there is currently no effective treatment for glioblastoma. Recently, the number of immunotherapeutic strategies has been tested for malignant brain tumors. Invariant natural killer T (iNKT) cells play an important role in anti-tumor immunity. To address if iNKT cells can target glioblastoma to exert anti-tumor activity, we assessed the expression of CD1d, an antigen-presenting molecule for iNKT cells, on glioblastoma cells. Glioblastoma cells from 10 of 15 patients expressed CD1d, and CD1d-positive glioblastoma cells pulsed with glycolipid ligand induced iNKT cell-mediated cytotoxicity in vitro. Although CD1d expression was low on glioblastoma stem-like cells, retinoic acid, which is the most common differentiating agent, upregulated CD1d expression in these cells and induced iNKT cell-mediated cytotoxicity. Moreover, intracranial administration of human iNKT cells induced tumor regression of CD1d-positive glioblastoma in orthotopic xenografts in NOD/Shi-scid IL-2RγKO (NOG) mice. Thus, CD1d expression represents a novel target for NKT cell-based immunotherapy for glioblastoma patients.

scholarly journals SIRT2 Contributes to the Resistance of Melanoma Cells to the Multikinase Inhibitor Dasatinib

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 673 ◽  
Author(s):  
Iwona Karwaciak ◽  
Anna Sałkowska ◽  
Kaja Karaś ◽  
Marta Sobalska-Kwapis ◽  
Aurelia Walczak-Drzewiecka ◽  
...  
Keyword(s):  
Regulation Of Gene Expression ◽  
Molecular Targets ◽  
Neutral Red ◽  
Melanoma Cells ◽  
Multikinase Inhibitor ◽  
Promising Target ◽  
Cell Metastasis ◽  
Genes Encoding ◽  
Basic Functions

Malignant melanoma is the most aggressive skin cancer and can only be cured if detected early. Unfortunately, later stages of the disease do not guarantee success due to the rapid rate of melanoma cell metastasis and their high resistance to applied therapies. The search for new molecular targets and targeted therapy may represent the future in the development of effective methods for combating this cancer. SIRT2 is a promising target; thus, we downregulated SIRT2 expression in melanoma cells in vertical growth and metastatic phases and demonstrated that sirtuin acts as regulator of the basic functions of melanoma cells. A detailed transcriptomic analysis showed that SIRT2 regulates the expression of multiple genes encoding the tyrosine kinase pathways that are molecular targets of dasatinib. Indeed, cells with low SIRT2 expression were more susceptible to dasatinib, as demonstrated by multiple techniques, e.g., neutral red uptake, 3/7 caspase activity, colony formation assay, and in vitro scratch assay. Furthermore, these cells showed an altered phosphorylation profile for proteins playing roles in the response to dasatinib. Thus, our research indicates new, previously unknown SIRT2 functions in the regulation of gene expression, which is of key clinical significance.

scholarly journals Efficacy of Ceftriaxone, Cefepime, Doxycycline, Ciprofloxacin, and Combination Therapy for Vibrio vulnificus Foodborne Septicemia

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Sonya A. Trinh ◽  
Hannah E. Gavin ◽  
Karla J. F. Satchell
Keyword(s):  
Combination Therapy ◽  
Vibrio Vulnificus ◽  
Survival Rates ◽  
Control Group ◽  
Content Type ◽  
Infection Models ◽  
Gram Negative Organisms ◽  
Foodborne Infection

ABSTRACT Foodborne Vibrio vulnificus infections are associated with higher rates of sepsis and mortality than wound infections; however, antibiotic efficacy studies have not been performed in foodborne infection models. The efficacies of ceftriaxone, cefepime, doxycycline, ciprofloxacin, and combination therapy were assessed in V. vulnificus intestinal infection in mice in order to model foodborne infections. In accordance with prior studies of cefotaxime, cefepime was synergistic with doxycycline and ciprofloxacin in vitro; combination therapy significantly decreased bacterial growth, by ≥2 log10 units, from that with antibiotic monotherapy (P < 0.01). In vivo, survival rates in the ceftriaxone (50%), doxycycline (79%), and ciprofloxacin (80%) groups were significantly higher than those in the control group (0%) (P < 0.0001). Survival was significantly higher with ceftriaxone-doxycycline (91%) or ceftriaxone-ciprofloxacin (100%) therapy than with ceftriaxone (50%) (P ≤ 0.05). Survival with cefepime-doxycycline (96%) or cefepime-ciprofloxacin (90%) therapy was significantly higher than that with cefepime alone (20%) (P < 0.001). There was no difference in survival between the combination therapy groups. Thus, we conclude that combination therapy was the most effective treatment for foodborne V. vulnificus septicemia. In a septic patient with a recent ingestion of raw seafood, cefepime in combination with doxycycline or ciprofloxacin should be initiated for coverage of resistant Gram-negative organisms and V. vulnificus pending a microbiological diagnosis. Once a diagnosis of foodborne V. vulnificus septicemia is established, treatment can safely transition to ceftriaxone in combination with doxycycline or ciprofloxacin.

scholarly journals Comparative Proteomic Study of the Antiproliferative Activity of Frog Host-Defence Peptide Caerin 1.9 and Its Additive Effect with Caerin 1.1 on TC-1 Cells Transformed with HPV16 E6 and E7

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Guoying Ni ◽  
Di Liang ◽  
Scott F. Cummins ◽  
Shelley F. Walton ◽  
Shu Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumour Microenvironment ◽  
Additive Effect ◽  
Host Defence ◽  
Signalling Pathways ◽  
Hpv16 E6 ◽  
Cytokines And Chemokines ◽  
Glandular Secretion ◽  
E6 And E7

Caerin is a family of peptides isolated from the glandular secretion of Australian tree frogs, the genusLitoria, and has been previously shown to have anticancer activity against several cancer cells. In this work, we used two host-defence peptides, caerin 1.1 and caerin 1.9, to investigate their ability to inhibit a murine derived TC-1 cell transformed with human papillomavirus 16 E6 and E7 growthin vitro. Caerin 1.9 inhibits TC-1 cell proliferation, although inhibition is more pronounced when applied in conjunction with caerin 1.1. To gain further insights into the antiproliferative mechanisms of caerin 1.9 and its additive effect with caerin 1.1, we used a proteomics strategy to quantitatively examine (i) the changes in the protein profiles of TC-1 cells and (ii) the excretory-secretory products of TC-1 cells following caerin peptides treatment. Caerin 1.9 treatment significantly altered the abundance of several immune-related proteins and related pathways, such as the Tec kinase and ILK signalling pathways, as well as the levels of proinflammatory cytokines and chemokines. In conclusion, caerin peptides inhibit TC-1 cell proliferation, associated with modification in signalling pathways that would change the tumour microenvironment which is normally immune suppressive.

scholarly journals Siglec-15 Promotes Tumor Progression in Osteosarcoma via DUSP1/MAPK Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Meng-ke Fan ◽  
Guo-chuan Zhang ◽  
Wei Chen ◽  
Li-li Qi ◽  
Ming-fang Xie ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Migration And Invasion ◽  
Control Group ◽  
Aberrant Expression ◽  
Mesenchymal Transition ◽  
Novel Target

Recurrence and metastasis are important features of osteosarcoma (OS) that cause its poor prognosis. Aberrant expression of Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) has been reported in various kinds of cancers. However, the expression and function of Siglec-15 in OS remain unclear. In cultured OS cells (143B cells and MNNG/HOS cells) and their xenograft mouse models, we found that downregulation of Siglec-15 could inhibit the proliferation, migration and invasion of by inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Conversely, Siglec-15 overexpression promoted the growth, migration and invasion of OS cells in a significant manner. Then, we screened a number of differentially expressed genes (DEGs) between Siglec-15-knockdown group and control group by RNA-Seq assay. Among these DEGs, we found that dual-specificity phosphatase 1 (DUSP1/MKP1) was significantly downregulated after Siglec-15 silencing. We investigated the DUSP1 functions in influencing OS cells’ biology, and found that the proliferation, migration and invasion of OS cells were promoted by overexpressing DUSP1 and crucially, the proliferation, migration and invasion of Siglec-15-knockdown OS cells were rescued by overexpressing DUSP1. Mechanically, we further showed that DUSP1-mediated inhibition of p38/MAPK and JNK/MAPK expression was attenuated when Siglec-15 expression was inhibited, suggesting that Siglec-15 promotes the malignant progression of OS cells by suppressing DUSP1-mediated suppression of the MAPK pathway. Moreover, we showed that both Siglec-15 and DUSP1 were highly expressed in human OS tissues by immunohistochemistry. High Siglec-15 expression was associated with OS lung metastasis, and high DUSP1 expression was associated with the high Enneking stage. Kaplan–Meier analysis indicated that high expression of Siglec-15 could predict poor prognosis of OS patients. Altogether, these results showed that Siglec-15 expression promoted OS development and progression by activating DUSP1 and might be a novel target in OS treatment.

Moxifloxacin (BAY12-8039), a New 8-Methoxyquinolone, Is Active in a Mouse Model of Tuberculosis

1999 ◽  
Vol 43 (1) ◽  
pp. 85-89 ◽  
Author(s):  
Eishi Miyazaki ◽  
Miki Miyazaki ◽  
Jong Min Chen ◽  
Richard E. Chaisson ◽  
William R. Bishai
Keyword(s):  
Combination Therapy ◽  
High Titer ◽  
Clinical Strain ◽  
Control Group ◽  
Multiple Drug ◽  
Time Curve ◽  
Highly Effective ◽  
Drug Regimens ◽  
Highly Virulent

ABSTRACT Moxifloxacin (BAY12-8039) is a new 8-methoxyquinolone shown to be active against Mycobacterium tuberculosis in vitro. We tested moxifloxacin for activity in mice against M. tuberculosis CSU93, a highly virulent, recently isolated clinical strain. The MIC of moxifloxacin for the CSU93 strain was 0.25 μg/ml. The serum moxifloxacin concentration after oral administration in mice peaked within 0.25 h, reaching 7.8 μg/ml with doses of 100 mg/kg of body weight; the maximum concentration and the analysis of the area under the concentration-time curve revealed dose dependency. When mice were infected with a sublethal inoculum of mycobacteria and then treated with moxifloxacin at 100 mg/kg per day for 8 weeks, the log10 CFU counts in the organs of treated mice were significantly lower than those for the control group (0.6 ± 0.2 versus 5.6 ± 0.3 in the lungs and 1.5 ± 0.7 versus 4.9 ± 0.5 in the spleens, respectively;P < 0.001 in both organs). The effectiveness of moxifloxacin monotherapy was comparable to that seen in mice receiving isoniazid alone. Combination therapy with moxifloxacin plus isoniazid was superior to that with moxifloxacin or with isoniazid alone in reducing bacillary counts in the organs studied. Using a sensitive broth-passage subculture method, we demonstrated that 8 weeks of treatment with moxifloxacin (100 mg/kg per day) or with moxifloxacin plus isoniazid (100 mg/kg and 25 mg/kg, respectively, per day) sterilized the lungs in seven of eight and in eight of eight mice, respectively. Among surviving bacilli isolated from animals infected with a high-titer inoculum and treated for 7 weeks with low-dose moxifloxacin (20 mg/kg per day), breakthrough resistance to moxifloxacin was not observed. These results indicate that moxifloxacin is highly effective in reducing M. tuberculosis infection in mice and has activity comparable to that of isoniazid. Combination therapy with moxifloxacin and isoniazid was highly effective, suggesting that moxifloxacin may be useful in multiple-drug regimens for human tuberculosis.

The Histopathological Effect of Thymoquinone on Experimentally Induced Rhinosinusitis in Rats

2011 ◽  
Vol 25 (6) ◽  
pp. e268-e272 ◽  
Author(s):  
Cemal Cingi ◽  
Görkem Eskiizmir ◽  
Dilek Burukoğlu ◽  
Nagehan Erdoğmuş ◽  
Ahmet Ural ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Platelet Activating Factor ◽  
Negative Control Group ◽  
Negative Control ◽  
Control Group ◽  
Control Groups ◽  
Histopathological Features ◽  
Histopathological Effect ◽  
Significant Difference ◽  
Experimentally Induced

Background Rhinosinusitis is a common disorder and its treatment includes a variety of topical and systemic drugs. This study was designed to determine the histopathological effect of thymoquinone on experimentally induced rhinosinusitis in rats. Methods Sixty rats were randomly allocated into 3 test and 2 control groups, each of which consisted of 12 animals. The rhinosinusitis model was induced using intranasal application of platelet-activating factor. In test groups, the animals were separated into groups: (1) rhinosinusitis-antibiotherapy, (2) rhinosinusitis-thymoquinone, (3) rhinosinusitis-combination therapy. The positive and negative control groups were defined: rhinosinusitis group without any treatment and the group without rhinosinusitis, respectively. The histopathological features (vascular congestion, inflammation, and epithelial injury) in nasal respiratory and olfactory mucosa of animals were examined and graded according to their severity. A quantitative and statistical analysis of histopathological features was performed. Results All histopathological features showed statistically significant differences between negative and positive control groups, respectively. Conversely, neither the group with rhinosinusitis-antibiotherapy nor the group with rhinosinusitis-thymoquinone had a statistically significant difference with the negative control group. Moreover, none of the histopathological features showed a statistically significant difference, when the group with rhinosinusitis-antibiotherapy and the group with rhinosinusitis-thymoquinone were compared. A statistically significant difference was not determined when the group with rhinosinusitis-combination therapy was compared with the group with rhinosinusitis-thymoquinone. The histopathological features did not show a statistically significant difference between the group with combination therapy and the negative control Conclusion Thymoquinone is a promising bioactive agent for the treatment of rhinosinusitis, and its histopathological effect is as equivalent as an antibiotic.

scholarly journals Metastatic melanoma cells are selective affected in vitro by Atropa belladonna 200 c.

2021 ◽  
Vol 17 (2) ◽  
pp. 19-20
Author(s):  
Maria Luiza Ferreira dos Santos ◽  
Jenifer Pendiuk Gonçalves ◽  
Viviana Stephanie Costa Gagosian ◽  
Gustavo Rodrigues Rossi ◽  
Edvaldo Da Silva Trindade ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Metastatic Melanoma ◽  
Survival Rates ◽  
Melanoma Cells ◽  
Chemotherapeutic Agents ◽  
Control Group ◽  
P Value ◽  
Atropa Belladonna ◽  
Antitumor Effects

Abstract Background: Cancers are among the top 10 causes of death worldwide. Melanoma is a skin cancer originated from mutations on melanocytes. Transformed melanocytes can migrate and invade tissues in a process called metastasis. When early diagnosed, melanoma is curable by surgical excision. However, when metastatic, cells are refractory to existing therapies and patient survival rates are low. New therapeutic interventions with effective results on melanoma cells that could increase long term patients’ survival rates are needed. Over the past decade our group has been using cell-based models to determine highly diluted solutions effects. Several compounds have been tested on normal and tumor cells with promising results that could indicate the efficacy of homeopathy on selected cases. Aims: To investigate Atropa belladonna 200 c (Bell200c) in vitro antitumor effects on B16-F10 metastatic murine melanoma cells and its toxicity on Balb/3T3 normal murine fibroblasts. Methodology: Atropa belladonna 200c was produced and kindly donated by “Homeoterápica” compounding pharmacy (Curitiba, Brazil). Cells were treated for up to 72 hours. Assays to determine cytotoxicity, as well as functional and molecular cell patterns were carried out following standard protocols. Water treated cells were used as control group. All data were submitted to Shapiro-Wilk normality test followed by either Mann-Whitney or t-test. P value < 0.05 was considered significant. Results and discussion: Cancer cells accelerated proliferation rates are often target for chemotherapeutic agents. Bell200c modulated cell cycle, leading to a decreased melanoma cell proliferation (44% less cells then control), and an increase in apoptotic cells number. If unspecific, those effects can lead to undesirable toxicity. Amazingly, no effects on fibroblast proliferation and death were observed. Melanoma cells malignancy was also affected, as the following tumor progression related features were modulated. Melanin production was higher in treated cells. N-cadherin and CD44 expression were statistically decreased. Clonogenic capacity was decreased by 35%. Here we have demonstrated Bell200c selective effects on melanoma cells with remarkable capacity of impairing metastatic melanoma characteristics. Conclusion: Atropa belladonna has a prospective use in metastatic melanoma patients as a potential tumor progression regulator. Keywords: in vitro testing, high dilution, B16-F10, melanoma.

Ancylostoma caninum Anticoagulant Peptide Blocks Metastasis In Vivo and Inhibits Factor Xa Binding to Melanoma Cells In Vitro

1998 ◽  
Vol 79 (05) ◽  
pp. 1041-1047 ◽  
Author(s):  
Kathleen M. Donnelly ◽  
Michael E. Bromberg ◽  
Aaron Milstone ◽  
Jennifer Madison McNiff ◽  
Gordon Terwilliger ◽  
...  
Keyword(s):  
Active Site ◽  
Thrombin Generation ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Melanoma Cells ◽  
Factor V ◽  
Ancylostoma Caninum ◽  
Metastatic Activity

SummaryWe evaluated the in vivo anti-metastatic activity of recombinant Ancylostoma caninum Anticoagulant Peptide (rAcAP), a potent (Ki = 265 pM) and specific active site inhibitor of human coagulation factor Xa originally isolated from bloodfeeding hookworms. Subcutaneous injection of SCID mice with rAcAP (0.01-0.2 mg/mouse) prior to tail vein injection of LOX human melanoma cells resulted in a dose dependent reduction in pulmonary metastases. In order to elucidate potential mechanisms of rAcAP’s anti-metastatic activity, experiments were carried out to identify specific interactions between factor Xa and LOX. Binding of biotinylated factor Xa to LOX monolayers was both specific and saturable (Kd = 15 nM). Competition experiments using antibodies to previously identified factor Xa binding proteins, including factor V/Va, effector cell protease receptor-1, and tissue factor pathway inhibitor failed to implicate any of these molecules as significant binding sites for Factor Xa. Functional prothrombinase activity was also supported by LOX, with a half maximal rate of thrombin generation detected at a factor Xa concentration of 2.4 nM. Additional competition experiments using an excess of either rAcAP or active site blocked factor Xa (EGR-Xa) revealed that most of the total factor Xa binding to LOX is mediated via interaction with the enzyme’s active site, predicting that the vast majority of cell-associated factor Xa does not participate directly in thrombin generation. In addition to establishing two distinct mechanisms of factor Xa binding to melanoma, these data raise the possibility that rAcAP’s antimetastatic effect in vivo might involve novel non-coagulant pathways, perhaps via inhibition of active-site mediated interactions between factor Xa and tumor cells.

Sign in / Sign up

Export Citation Format

Share Document