scholarly journals Cisplatin-Induced Giant Cells Formation Is Involved in Chemoresistance of Melanoma Cells

2020 ◽  
Vol 21 (21) ◽  
pp. 7892
Author(s):  
Chien-Hui Weng ◽  
Chieh-Shan Wu ◽  
Jian-Ching Wu ◽  
Mei-Lang Kung ◽  
Ming-Hsiu Wu ◽  
...  
Keyword(s):  
Multiple Drug Resistance ◽  
Giant Cells ◽  
Melanoma Cells ◽  
Cell Diameter ◽  
Multiple Drug ◽  
Stem Cell Markers ◽  
Ki 67 ◽  
Cancer Stem Cell Markers

Melanoma is notoriously resistant to current cancer therapy. However, the chemoresistance mechanism of melanoma remains unclear. The present study unveiled that chemotherapy drug cisplatin induced the formation of giant cells, which exhibited enlargement in cell diameter and nucleus in mice and human melanoma cells. Giant cells were positive with melanoma maker S100 and cancer stem cell markers including ABCB5 and CD133 in vitro and in vivo. Moreover, giant cells retained the mitotic ability with expression of proliferation marker Ki-67 and exhibited multiple drug resistance to doxorubicin and actinomycin D. The mitochondria genesis/activities and cellular ATP level were significantly elevated in giant cells, implicating the demand for energy supply. Application of metabolic blockers such as sodium azide or 2-deoxy glucose abolished the cisplatin-induced giant cells formation and expression of cancer stemness markers. The present study unveils a novel chemoresistance mechanism of melanoma cells via size alteration and the anti-neoplastic strategy by targeting giant cells.

scholarly journals Treatment with Uncaria tomentosa Promotes Apoptosis in B16-BL6 Mouse Melanoma Cells and Inhibits the Growth of B16-BL6 Tumours

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1066
Author(s):  
Ali Zari ◽  
Hajer Alfarteesh ◽  
Carly Buckner ◽  
Robert Lafrenie
Keyword(s):  
Tumour Size ◽  
Melanoma Cells ◽  
Tunel Staining ◽  
Aqueous Extracts ◽  
Ki 67 ◽  
Uncaria Tomentosa ◽  
Mouse Melanoma ◽  
Anti Cancer

Uncaria tomentosa is a medicinal plant native to Peru that has been traditionally used in the treatment of various inflammatory disorders. In this study, the effectiveness of U. tomentosa as an anti-cancer agent was assessed using the growth and survival of B16-BL6 mouse melanoma cells. B16-BL6 cell cultures treated with both ethanol and phosphate-buffered saline (PBS) extracts of U. tomentosa displayed up to 80% lower levels of growth and increased apoptosis compared to vehicle controls. Treatment with ethanolic extracts of Uncaria tomentosa were much more effective than treatment with aqueous extracts. U. tomentosa was also shown to inhibit B16-BL6 cell growth in C57/bl mice in vivo. Mice injected with both the ethanolic and aqueous extracts of U. tomentosa showed a 59 ± 13% decrease in B16-BL6 tumour weight and a 40 ± 9% decrease in tumour size. Histochemical analysis of the B16-BL6 tumours showed a strong reduction in the Ki-67 cell proliferation marker in U. tomentosa-treated mice and a small, but insignificant increase in terminal transferase dUTP nick labelling (TUNEL) staining. Furthermore, U. tomentosa extracts reduced angiogenic markers and reduced the infiltration of T cells into the tumours. Collectively, the results in this study concluded that U. tomentosa has potent anti-cancer activity that significantly inhibited cancer cells in vitro and in vivo.

scholarly journals Promising Recent Strategies with Potential Clinical Translational Value to Combat Antibacterial Resistant Surge

Medicines ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. 21 ◽  
Author(s):  
Partha Karmakar ◽  
Vishwanath Gaitonde
Keyword(s):  
Small Molecule ◽  
Multiple Drug Resistance ◽  
Resistance Mechanism ◽  
Multiple Drug ◽  
Antibacterial Efficacy ◽  
Small Particles ◽  
Near Future ◽  
Metal Polymer

Multiple drug resistance (MDR) for the treatment of bacterial infection has been a significant challenge since the beginning of the 21st century. Many of the small molecule-based antibiotic treatments have failed on numerous occasions due to a surge in MDR, which has claimed millions of lives worldwide. Small particles (SPs) consisting of metal, polymer or carbon nanoparticles (NPs) of different sizes, shapes and forms have shown considerable antibacterial effect over the past two decades. Unlike the classical small-molecule antibiotics, the small particles are less exposed so far to the bacteria to trigger a resistance mechanism, and hence have higher chances of fighting the challenge of the MDR process. Until recently, there has been limited progress of clinical treatments using NPs, despite ample reports of in vitro antibacterial efficacy. In this review, we discuss some recent and unconventional strategies that have explored the antibacterial efficacy of these small particles, alone and in combination with classical small molecules in vivo, and demonstrate possibilities that are favorable for clinical translations in near future.

scholarly journals Patient-derived cell lines and orthotopic mouse model of peritoneal carcinomatosis recapitulate molecular and phenotypic features of human gastric adenocarcinoma

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Shumei Song ◽  
Yan Xu ◽  
Longfei Huo ◽  
Shuangtao Zhao ◽  
Ruiping Wang ◽  
...  
Keyword(s):  
Peritoneal Carcinomatosis ◽  
Gastric Adenocarcinoma ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Stem Cell Markers ◽  
Orthotopic Mouse Model ◽  
Cancer Stem Cell Markers ◽  
Phenotypic Features

Abstract Background Gastric adenocarcinoma with peritoneal carcinomatosis (PC) is therapy resistant and leads to poor survival. To study PC in depth, there is an urgent need to develop representative PC-derived cell lines and metastatic models to study molecular mechanisms of PC and for preclinical screening of new therapies. Methods PC cell lines were developed from patient-derived PC cells. The tumorigenicity and metastatic potential were investigated by subcutaneously (PDXs) and orthotopically. Karyotyping, whole-exome sequencing, RNA-sequencing, and functional studies were performed to molecularly define the cell lines and compare genomic and phenotypic features of PDX and donor PC cells. Results We established three PC cell lines (GA0518, GA0804, and GA0825) and characterized them in vitro. The doubling times were 22, 39, and 37 h for GA0518, GA0804, and GA0825, respectively. Expression of cancer stem cell markers (CD44, ALDH1, CD133 and YAP1) and activation of oncogenes varied among the cell lines. All three PC cell lines formed PDXs. Interestingly, all three PC cell lines formed tumors in the patient derived orthotopic (PDO) model and GA0518 cell line consistently produced PC in mice. Moreover, PDXs recapitulated transcriptomic and phenotypic features of the donor PC cells. Finally, these cell lines were suitable for preclinical testing of chemotherapy and target agents in vitro and in vivo. Conclusion We successfully established three patient-derived PC cell lines and an improved PDO model with high incidence of PC associated with malignant ascites. Thus, these cell lines and metastatic PDO model represent excellent resources for exploring metastatic mechanisms of PC in depth and for target drug screening and validation by interrogating GAC for translational studies.

scholarly journals Isolation and characterisation of virulent Serratia marcescens associated with a disease outbreak in farmed ornamental fish, Poecilia reticulata in Kerala, India

2017 ◽  
Vol 64 (4) ◽  
Author(s):  
Arathi Dharmaratnam ◽  
Raj Kumar ◽  
V. S. Basheer ◽  
Neeraj Sood ◽  
T. Raja Swaminathan ◽  
...  
Keyword(s):  
Serratia Marcescens ◽  
Poecilia Reticulata ◽  
Multiple Drug Resistance ◽  
Clinical Signs ◽  
Ornamental Fish ◽  
Multiple Drug ◽  
Rrna Gene ◽  
Biochemical Tests

Pathogenic strain of Serratia marcescens (NPSM-1) with multiple drug resistance was isolated from guppy Poecilia reticulata with clinical signs of fin rot and was confirmed by biochemical tests and 16S rRNA gene sequencing. The extra cellular proteins (ECP) of the bacteria exhibited marked cytotoxic activity in vitro on Cyprinus carpio koi fin (CCKF) cell line. The in vivo challenge studies confirmed that the isolate was highly pathogenic to fish when the fishes were injected with1 x 104 CFU/fish and the same bacterium was re-isolated from infected fish, post-challenge. S. marcescens produced large zones of haemolysis on 10% sheep blood agar. The bacteria was found to carry virulence genes; extracellular metalloprotease gene (Pr596) and AHL synthase gene (SpnI). The bacterial isolate was tested to determine sensitivity against 16 antibiotics and was sensitive to only 5 viz., cefixime, chloramphenicol, ciprofloxacin, gentamycin and erythromycin. The study indicates that S. marcescens can cause disease in ornamental fish and the bacterium being a known human pathogen, may also cause infections in humans having direct contact with infected fishes. This is the first report describing S. marcescens as a pathogen of freshwater ornamental fish in India.

scholarly journals Phenotypic alterations in liver cancer cells induced by mechanochemical disruption

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hakm Y. Murad ◽  
Emma P. Bortz ◽  
Heng Yu ◽  
Daishen Luo ◽  
Gray M. Halliburton ◽  
...  
Keyword(s):  
Tumor Regression ◽  
Mechanical Vibration ◽  
Intermediate Stage ◽  
High Intensity Focused Ultrasound ◽  
Hematogenous Metastasis ◽  
Stem Cell Markers ◽  
Health Crisis ◽  
Cancer Stem Cell Markers

AbstractHepatocellular carcinoma (HCC) is a highly fatal disease recognized as a growing global health crisis worldwide. Currently, no curative treatment is available for early-to-intermediate stage HCC, characterized by large and/or multifocal tumors. If left untreated, HCC rapidly progresses to a lethal stage due to favorable conditions for metastatic spread. Mechanochemical disruption of cellular structures can potentially induce phenotypic alterations in surviving tumor cells that prevent HCC progression. In this paper, HCC response to mechanical vibration via high-intensity focused ultrasound and a chemical disruptive agent (ethanol) was examined in vitro and in vivo. Our analysis revealed that mechanochemical disruption caused a significant overproduction of reactive oxygen species (ROS) in multiple HCC cell lines (HepG2, PLC/PRF/5, and Hep3B). This led to a decrease in cell viability and long-term proliferation due to increased expression and activity of death receptors TNFR1 and Fas. The cells that survived mechanochemical disruption had a reduced expression of cancer stem cell markers (CD133, CD90, CD49f) and a diminished colony-forming ability. Mechanochemical disruption also impeded HCC migration and their adhesion to vascular endothelium, two critical processes in hematogenous metastasis. The HCC transformation to a non-tumorigenic phenotype post mechanochemical disruption was confirmed by a lack of tumor spheroid formation in vitro and complete tumor regression in vivo. These results show that mechanochemical disruption inhibits uncontrolled proliferation and reduces tumorigenicity and aggressiveness of HCC cells through ROS overproduction and associated activation of TNF- and Fas-mediated cell death signaling. Our study identifies a novel curative therapeutic approach that can prevent the development of aggressive HCC phenotypes.

scholarly journals Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer

2020 ◽  
Author(s):  
T.G. Arnason ◽  
V. MacDonald-Dickinson ◽  
J.F. Davies ◽  
L. Lobanova ◽  
C. Gaunt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Multiple Drug Resistance ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Multiple Drug ◽  
Anaphase Promoting Complex ◽  
Insulin Sensitizer

ABSTRACTLike humans, canines spontaneously develop lymphomas that are treated by chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and tumor accessibility make them excellent models to study MDR mechanisms. We previously demonstrated that adjunct treatment of in vitro MDR cell lines with insulin-sensitizers effectively restored MDR chemosensitivity and prevented MDR development. This study extends the use of an insulin-sensitizer to clinical and tumor responses in vivo in volunteer canines with MDR lymphoma, including assessing changes in MDR protein biomarkers and global gene expression. Longitudinal tumor sampling and analysis of MDR cases throughout treatment allowed a correlation between in vivo molecular mechanisms and clinical responsiveness. We found reduced MDR biomarkers within all tumors, yet only one canine entered clinical remission. Analysis of tumor samples during remission and relapse allowed comparison of gene expression profiles. This revealed the Anaphase Promoting Complex (APC), a ubiquitin-E3 ligase regulating cell cycle progression, was impaired during chemoresistance/MDR and restored during remission. Validating in vitro tests restored MDR chemosensitivity upon APC activation, supporting the idea that APC activity is an important underlying cellular mechanism associated with treatment resistance, and a novel potential therapeutic target.

scholarly journals Crizotinib and Doxorubicin Cooperatively Reduces Drug Resistance by Mitigating MDR1 to Increase Hepatocellular Carcinoma Cells Death

2021 ◽  
Vol 11 ◽  
Author(s):  
Ming Shao ◽  
Run Shi ◽  
Zhen-Xing Gao ◽  
Shan-Shan Gao ◽  
Jing-Feng Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Cell Death ◽  
Kinase Inhibitor ◽  
Multiple Drug Resistance ◽  
Autophagic Cell Death ◽  
Multiple Drug ◽  
Parp 1

As the sixth most lethal cancers worldwide, hepatocellular carcinoma (HCC) has been treated with doxorubicin (Dox) for decades. However, chemotherapy resistance, especially for Dox is an even more prominent problem due to its high cardiotoxicity. To find a regimen to reduce Dox resistance, and identify the mechanisms behind it, we tried to identify combination of drugs that can overcome drug resistance by screening tyrosine kinase inhibitor(s) with Dox with various HCC cell lines in vitro and in vivo. We report here that combination of Crizo and Dox has a synergistic effect on inducing HCC cell death. Accordingly, Crizo plus Dox increases Dox accumulation in nucleus 3-16 times compared to Dox only; HCC cell death enhanced at least 50% in vitro and tumor weights reduced ranging from 35 to 65%. Combining these two drugs reduces multiple drug resistance 1 (MDR1) protein as a result of activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), which phosphorylates eIF2α, leading to protein translational repression. Additionally, PERK stimulation activates C-Jun terminal kinase (JNK), resulting in accumulation of unfused autophagosome to enhance autophagic cell death via Poly-ADP-ribosyltransferase (PARP-1) cleavage. When the activity of PERK or JNK is blocked, unfused autophagosome is diminished, cleaved PARP-1 is reduced, and cell death is abated. Therefore, Crizo plus Dox sensitize HCC drug resistance by engaging PERK-p- eIF2α-MDR1, and kill HCC cells by engaging PERK-JNK- autophagic cell death pathways. These newly discovered mechanisms of Crizo plus Dox not only provide a potential treatment for HCC but also point to an approach to overcome MDR1 related drug resistance in other cancers.

scholarly journals Transfer and expression of the human multidrug resistance gene in mouse erythroleukemia cells

Blood ◽  
1992 ◽  
Vol 80 (12) ◽  
pp. 3106-3111 ◽  
Author(s):  
E DelaFlor-Weiss ◽  
C Richardson ◽  
M Ward ◽  
A Himelstein ◽  
L Smith ◽  
...  
Keyword(s):  
Protein Expression ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
Drug Selection ◽  
Erythroid Cells ◽  
Multidrug Resistance Gene ◽  
Erythroleukemia Cells ◽  
Mouse Erythroleukemia

Abstract Gene therapy in humans requires the transplantation of genetically modified cells, and it is important to select only those cells capable of expressing high levels of protein from the transferred gene. Expression of the human multiple drug resistance (MDR) gene confers resistance to a variety of compounds in vitro and in vivo. To determine the feasibility of conferring recipient erythroid cells with the MDR phenotype, we have transduced mouse erythroleukemia cells (MELC) with the MDR gene in a retroviral vector. We show here that MELC clones resistant to exposure to colchicine (an MDR-responsive agent) can be isolated, and demonstrate high levels of MDR RNA and protein expression. Increasing doses of colchicine increase the level of MDR RNA and protein expression significantly. These results indicate that it is possible to transfer and express the human MDR phenotype in mouse erythroid cells by retrovirally mediated gene transfer, and that drug selection can be used to enrich or purify populations of cells containing and expressing this gene.

scholarly journals In vivo activity of anprocide alone, and in vitro activity in combination with conventional antibiotics against Staphylococcus aureus and Staphylococcus epidermidis biofilms

2009 ◽  
Vol 58 (9) ◽  
pp. 1203-1206 ◽  
Author(s):  
Robin K. Pettit ◽  
Christine A. Weber ◽  
Stacey B. Lawrence ◽  
George R. Pettit ◽  
Melissa J. Kean ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Drug Resistance ◽  
Murine Model ◽  
Staphylococcus Epidermidis ◽  
Multiple Drug Resistance ◽  
Multiple Drug ◽  
In Vitro Activity ◽  
Conventional Antibiotics

The alarming spread of multiple drug resistance in Staphylococcus aureus, combined with the frequent occurrence of S. aureus and Staphylococcus epidermidis in biofilm-type infections, indicates a growing need for new therapies. The experimental steroidal amide anprocide [3β-acetoxy-17β-(l-prolyl)amino-5α-androstane] significantly reduced c.f.u. ml−1 per suture (P <0.0001) in a murine model of topical S. aureus infection. In chequerboard assays with planktonic-grown S. aureus and S. epidermidis, anprocide was synergistic with bacitracin, oxacillin, clindamycin or ceftriaxone. Anprocide was also synergistic in combination with bacitracin or oxacillin against some isolates of biofilm-grown S. aureus and S. epidermidis.

scholarly journals RETRACTED ARTICLE: Functional screen analysis reveals miR-3142 as central regulator in chemoresistance and proliferation through activation of the PTEN-AKT pathway in CML

2017 ◽  
Vol 8 (5) ◽  
pp. e2830-e2830 ◽  
Author(s):  
Lifen Zhao ◽  
Yujia Shan ◽  
Bing Liu ◽  
Yang Li ◽  
Li Jia
Keyword(s):  
Colony Formation ◽  
Multiple Drug Resistance ◽  
Chemotherapy Resistance ◽  
K562 Cells ◽  
Akt Pathway ◽  
Multiple Drug ◽  
Akt Inhibitor ◽  
Enhanced Sensitivity

Abstract Chronic myeloid leukemia (CML) is caused by the constitutively active BCR-ABL tyrosine kinase. Although great progress has been made for improvement in clinical treatment during the past decades, it is common for patients to develop chemotherapy resistance. Therefore, further exploring novel therapeutic strategies are still crucial for improving disease outcome. MicroRNAs (miRNAs) represent a novel class of genes that function as negative regulators of gene expression. Recently, miRNAs have been implicated in several cancers. Previously, we identified 41 miRNAs that were dysregulated in resistant compared with adriamycin (ADR)-sensitive parental cells in CML. In the present study, we reported that miR-3142 are overexpressed in ADR-resistant K562/ADR cells and CML/multiple drug resistance patients, as compared with K562 cells and CML patients. Upregulation of miR-3142 in K562 cells accelerated colony formation ability and enhanced resisitance to ADR in vitro. Conversely, inhibition of miR-3142 expression in K562/ADR cells decreased colony-formation ability and enhanced sensitivity to ADR in vitro and in vivo. Significantly, our results showed miR-3142-induced ADR resistance through targeting phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which led to downregulation of PTEN protein and activation of PI3 kinase (PI3K)/Akt pathway. Inhibition of Akt using Akt inhibitor or introduction of PTEN largely abrogated miR-3142-induced resistance. These findings indicated that miR-3142 induces cell proliferation and ADR resistance primarily through targeting the PTEN/PI3K/Akt pathway and implicate the potential application of miR-3142 in cancer therapy.

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