scholarly journals Targeting Glutathione-S Transferase Enzymes in Musculoskeletal Sarcomas: A Promising Therapeutic Strategy

2011 ◽  
Vol 34 (3) ◽  
pp. 131-145 ◽  
Author(s):  
Michela Pasello ◽  
Maria Cristina Manara ◽  
Francesca Michelacci ◽  
Marilù Fanelli ◽  
Claudia Maria Hattinger ◽  
...  
Keyword(s):  
Cell Lines ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Therapeutic Option ◽  
In Vivo Studies ◽  
Whole Body ◽  
Drug Resistant ◽  
Glutathione S Transferase ◽  
Positive Interaction

Recent studies have indicated that targeting glutathione-S-transferase (GST) isoenzymes may be a promising novel strategy to improve the efficacy of conventional chemotherapy in the three most common musculoskeletal tumours: osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. By using a panel of 15 drug-sensitive and drug-resistant human osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma cell lines, the efficay of the GST-targeting agent 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX) has been assessed and related to GST isoenzymes expression (namely GSTP1, GSTA1, GSTM1, and MGST). NBDHEX showed a relevantin vitroactivity on all cell lines, including the drug-resistant ones and those with higher GSTs levels. Thein vitroactivity of NBDHEX was mostly related to cytostatic effects, with a less evident apoptotic induction. NBDHEX positively interacted with doxorubicin, vincristine, cisplatin but showed antagonistic effects with methotrexate. In vivo studies confirmed the cytostatic efficay of NBDHEX and its positive interaction with vincristine in Ewing's sarcoma cells, and also indicated a positive effect against the metastatisation of osteosarcoma cells. The whole body of evidence found in this study indicated that targeting GSTs in osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma may be an interesting new therapeutic option, which can be considered for patients who are scarcely responsive to conventional regimens.

scholarly journals An Innovative Therapeutic Option for the Treatment of Skeletal Sarcomas: Elimination of Osteo- and Ewing’s Sarcoma Cells Using Physical Gas Plasma

2020 ◽  
Vol 21 (12) ◽  
pp. 4460 ◽  
Author(s):  
Josephine M. Jacoby ◽  
Silas Strakeljahn ◽  
Andreas Nitsch ◽  
Sander Bekeschus ◽  
Peter Hinz ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cell Lines ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Therapeutic Option ◽  
Bone Sarcoma ◽  
Atmospheric Plasma ◽  
Local Surgery ◽  
Release Assay ◽  
Sarcoma Cells

Osteosarcoma and Ewing’s sarcoma are the most common malignant bone tumors. Conventional therapies such as polychemotherapy, local surgery, and radiotherapy improve the clinical outcome for patients. However, they are accompanied by acute and chronic side effects that affect the quality of life of patients, motivating novel research lines on therapeutic options for the treatment of sarcomas. Previous experimental work with physical plasma operated at body temperature (cold atmospheric plasma, CAP) demonstrated anti-oncogenic effects on different cancer cell types. This study investigated the anti-cancer effect of CAP on two bone sarcoma entities, osteosarcoma and Ewing’s sarcoma, which were represented by four cell lines (U2-OS, MNNG/HOS, A673, and RD-ES). A time-dependent anti-proliferative effect of CAP on all cell lines was observed. CAP-induced alterations in cell membrane functionality were detected by performing a fluorescein diacetate (FDA) release assay and an ATP release assay. Additionally, modifications of the cell membrane and modifications in the actin cytoskeleton composition were examined using fluorescence microscopy monitoring dextran-uptake assay and G-/F-actin distribution. Furthermore, the CAP-induced induction of apoptosis was determined by TUNEL and active caspases assays. The observations suggest that a single CAP treatment of bone sarcoma cells may have significant anti-oncogenic effects and thus may be a promising extension to existing applications.

Arsenic Trioxide Shows Synergistic Anti-Myeloma Effects When Combined with Bortezomib and Melphalan In Vitro and Helps Overcome Resistance of Multiple Myeloma Cells to These Treatments in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2467-2467
Author(s):  
Richard A. Campbell ◽  
Haiming Chen ◽  
Daocheng Zhu ◽  
Janice C. Santos ◽  
Benjamin Bonavida ◽  
...  
Keyword(s):  
Arsenic Trioxide ◽  
Cell Lines ◽  
Combined Therapy ◽  
In Vivo Studies ◽  
Low Doses ◽  
Drug Resistant ◽  
Early Results ◽  
Post Implantation

Abstract Arsenic trioxide (ATO) induces apoptosis of plasma cells through a number of mechanisms including inhibiting DNA binding by NF-κB. These results suggest that this agent may be synergistic when combined with other active anti-myeloma drugs. To evaluate this we examined the effect of ATO alone and in combination with anti-myeloma treatments evaluated in vitro with MTT assays and using our severe combined immunodeficient (SCID)-hu murine myeloma models. First, we determined the effects of combining ATO with bortezomib or melphalan on the myeloma cell lines RPMI8226 and U266. Cell proliferation assays demonstrated marked synergistic anti-proliferative effects of ATO at concentrations ranging from 5x10−5M – 5x10−9M and melphalan concentrations ranging from 3x10−5M – 3x10−9M. Similar effects were observed when these cell lines were treated with bortezomib and varying concentrations of ATO (5x10−5 M – 5x10−10 M). We also investigated the potential of ATO to increase the efficacy of anti-myeloma therapies in our SCID-hu murine model LAGλ–1 (Yang H et al. Blood 2002). Each SCID mouse was implanted with a 0.5 cm3 LAGλ–1 tumor fragment into the left hind limb muscle. Mice were treated with ATO alone at 6.0 mg/kg, 1.25 mg/kg, 0.25 mg/kg, and 0.05 mg/kg intraperitoneally (IP) daily x5/week starting 19 days post-implantation. Mice receiving the highest dose of ATO (6.0 mg/kg) showed marked inhibition of tumor growth and reduction of paraprotein levels while there was no effect observed in all other treatment groups. Next, 27 days following implantation of our LAGλ–1 intramuscular (IM) tumor, LAGλ–1 mice were treated with ATO (1.25 mg/kg) IP, bortezomib (0.25 mg/kg), or the combination of both drugs at these doses in the schedules outlined above. ATO or bortezomib treatment alone had no anti-myeloma effects at these low doses consistent with our previous results whereas there was a marked decrease in both tumor volume (57%) and paraprotein levels (53%) in mice receiving the combined therapy. The combination of melphalan and ATO was also evaluated in this model. LAGλ–1 bearing mice received therapy with melphalan IP x1/weekly at 12.0 mg/kg, 6.0 mg/kg, 0.6 mg/kg, and 0.06 mg/kg starting 22 days post-implantation and showed no anti-myeloma effects. Twenty-eight days following implantation of LAGλ–1 tumor, mice received ATO (1.25 mg/kg) or melphalan (0.6 mg/kg) alone at doses without anti-myeloma effects, or the combination of these agents at these doses. The animals treated with these drugs alone showed a similar growth and increase in paraprotein levels to control mice whereas the combination of ATO and melphalan at these low doses markedly suppressed the growth of the tumor by >50% and significantly reduced serum paraprotein levels. These in vitro and in vivo studies suggest that the addition of ATO to other anti-myeloma agents is likely to result in improved outcomes for patients with drug resistant myeloma. Based on these results, these combinations are now in clinical trials with promising early results for patients with drug resistant myeloma.

scholarly journals Discovery and Validation of a Compound to Target Ewing’s Sarcoma

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1553
Author(s):  
Ellie Esfandiari Nazzaro ◽  
Fahad Y. Sabei ◽  
Walter K. Vogel ◽  
Mohamad Nazari ◽  
Katelyn S. Nicholson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Apoptotic Cell ◽  
Intensive Therapy ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Cytotoxic Agents ◽  
Sarcoma Cell

Ewing’s sarcoma, characterized by pathognomonic t (11; 22) (q24; q12) and related chromosomal ETS family translocations, is a rare aggressive cancer of bone and soft tissue. Current protocols that include cytotoxic chemotherapeutic agents effectively treat localized disease; however, these aggressive therapies may result in treatment-related morbidities including second-site cancers in survivors. Moreover, the five-year survival rate in patients with relapsed, recurrent, or metastatic disease is less than 30%, despite intensive therapy with these cytotoxic agents. By using high-throughput phenotypic screening of small molecule libraries, we identified a previously uncharacterized compound (ML111) that inhibited in vitro proliferation of six established Ewing’s sarcoma cell lines with nanomolar potency. Proteomic studies show that ML111 treatment induced prometaphase arrest followed by rapid caspase-dependent apoptotic cell death in Ewing’s sarcoma cell lines. ML111, delivered via methoxypoly(ethylene glycol)-polycaprolactone copolymer nanoparticles, induced dose-dependent inhibition of Ewing’s sarcoma tumor growth in a murine xenograft model and invoked prometaphase arrest in vivo, consistent with in vitro data. These results suggest that ML111 represents a promising new drug lead for further preclinical studies and is a potential clinical development for the treatment of Ewing’s sarcoma.

c-kit Receptor Expression in Ewing’s Sarcoma: Lack of Prognostic Value but Therapeutic Targeting Opportunities in Appropriate Conditions

2003 ◽  
Vol 21 (10) ◽  
pp. 1952-1960 ◽  
Author(s):  
Katia Scotlandi ◽  
Maria Cristina Manara ◽  
Rosaria Strammiello ◽  
Lorena Landuzzi ◽  
Stefania Benini ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cell Lines ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Receptor Expression ◽  
In Vitro Growth ◽  
Es Cell ◽  
Primary Tumors ◽  
Sti 571

Purpose: Autocrine/paracrine stimulation of c-kit has been recently observed in Ewing’s sarcoma (ES) cell lines. In this study, we tested the prognostic and therapeutic role of the receptor in this tumor. Methods: One hundred one ES tumor biopsies were evaluated for the expression of c-kit by the avidin-biotin-peroxidase procedure. Effectiveness of STI-571 (Gleevec; Novartis, Basel, Switzerland), a selective inhibitor of specific tyrosine kinases, was analyzed with respect to in vitro growth and migration inhibition, as single agent or in combination with doxorubicin. Results: Approximately 30% of patients expressed c-kit in their primary tumors. No significant association between the expression of the receptor and the clinical outcome was observed. In vitro growth of ES cell lines showing high levels of c-kit demonstrated limited inhibition by exposure to STI-571 (10 μmol/L is required to obtain 40% to 50% of growth inhibition). A decrease of stem-cell factor–mediated ES cell migration was also found. The drug acted additively with doxorubicin in inhibiting ES cell growth. Conclusion: The negative prognostic findings and the limited in vitro therapeutic activity of STI-571 indicate that the putative aberrant signaling provided by c-kit overexpression may be dispensable for ES development and unlikely to constitute a critical therapeutic target. Accordingly, the dose of STI-571 required to give a significant ES growth inhibition is much higher than for those tumors in which mutations of c-kit constitute a relevant pathogenetic event. Nevertheless, in the subset of ES patients showing a high level of c-kit expression, the activity of the drug may be exploited in combination with standard therapy.

scholarly journals Exploiting Gangliosides for the Therapy of Ewing’s Sarcoma and H3K27M-Mutant Diffuse Midline Glioma

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 520
Author(s):  
Arthur Wingerter ◽  
Khalifa El Malki ◽  
Roger Sandhoff ◽  
Larissa Seidmann ◽  
Daniel-Christoph Wagner ◽  
...  
Keyword(s):  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Therapeutic Option ◽  
Intracranial Metastasis ◽  
Pediatric Tumor ◽  
Ganglioside Metabolism ◽  
Intermediate Expression ◽  
Diffuse Midline Glioma ◽  
Tumor Entities

The ganglioside GD2 is an important target in childhood cancer. Nevertheless, the only therapy targeting GD2 that is approved to date is the monoclonal antibody dinutuximab, which is used in the therapy of neuroblastoma. The relevance of GD2 as a target in other tumor entities remains to be elucidated. Here, we analyzed the expression of GD2 in different pediatric tumor entities by flow cytometry and tested two approaches for targeting GD2. H3K27M-mutant diffuse midline glioma (H3K27M-mutant DMG) samples showed the highest expression of GD2 with all cells strongly positive for the antigen. Ewing’s sarcoma (ES) samples also showed high expression, but displayed intra- and intertumor heterogeneity. Osteosarcoma had low to intermediate expression with a high percentage of GD2-negative cells. Dinutuximab beta in combination with irinotecan and temozolomide was used to treat a five-year-old girl with refractory ES. Disease control lasted over 12 months until a single partially GD2-negative intracranial metastasis was detected. In order to target GD2 in H3K27M-mutant DMG, we blocked ganglioside synthesis via eliglustat, since dinutuximab cannot cross the blood–brain barrier. Eliglustat is an inhibitor of glucosylceramide synthase, and it is used for treating children with Gaucher’s disease. Eliglustat completely inhibited the proliferation of primary H3K27M-mutant DMG cells in vitro. In summary, our data provide evidence that dinutuximab might be effective in tumors with high GD2 expression. Moreover, disrupting the ganglioside metabolism in H3K27M-mutant DMG could open up a new therapeutic option for this highly fatal cancer.

scholarly journals Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3487
Author(s):  
Yu-Ling Lu ◽  
Ming-Hsien Wu ◽  
Yi-Yin Lee ◽  
Ting-Chao Chou ◽  
Richard J. Wong ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Lines ◽  
Differentiated Thyroid Cancer ◽  
Xenograft Model ◽  
In Vivo Studies ◽  
Follicular Thyroid Cancer ◽  
Biomarker Analysis ◽  
Cancer Tumor

Differentiated thyroid cancer (DTC) patients are usually known for their excellent prognoses. However, some patients with DTC develop refractory disease and require novel therapies with different therapeutic mechanisms. Targeting Wee1 with adavosertib has emerged as a novel strategy for cancer therapy. We determined the effects of adavosertib in four DTC cell lines. Adavosertib induces cell growth inhibition in a dose-dependent fashion. Cell cycle analyses revealed that cells were accumulated in the G2/M phase and apoptosis was induced by adavosertib in the four DTC tumor cell lines. The sensitivity of adavosertib correlated with baseline Wee1 expression. In vivo studies showed that adavosertib significantly inhibited the xenograft growth of papillary and follicular thyroid cancer tumor models. Adavosertib therapy, combined with dabrafenib and trametinib, had strong synergism in vitro, and revealed robust tumor growth suppression in vivo in a xenograft model of papillary thyroid cancer harboring mutant BRAFV600E, without appreciable toxicity. Furthermore, combination of adavosertib with lenvatinib was more effective than either agent alone in a xenograft model of follicular thyroid cancer. These results show that adavosertib has the potential in treating DTC.

scholarly journals Characterization and Drug Resistance Patterns of Ewing's Sarcoma Family Tumor Cell Lines

PLoS ONE ◽  
2013 ◽  
Vol 8 (12) ◽  
pp. e80060 ◽  
Author(s):  
William A. May ◽  
Rita S. Grigoryan ◽  
Nino Keshelava ◽  
Daniel J. Cabral ◽  
Laura L. Christensen ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tumor Cell ◽  
Cell Lines ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Tumor Cell Lines ◽  
Resistance Patterns

Surviving cancer or future motherhood? Both are possible: an Ewing sarcoma case in an 8-year-old girl

2021 ◽  
Vol 14 (4) ◽  
pp. e241417
Author(s):  
Tânia Ascensão ◽  
Maria Inês Marques ◽  
Helena Barros Leite
Keyword(s):  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Reproductive Potential ◽  
Adult Life ◽  
Vitro Fertilization ◽  
Successful Case ◽  
Paediatric Age ◽  
Reproductive Cycles ◽  
Uneventful Pregnancy

Ewing’s sarcoma is an aggressive tumour, common in paediatric age, in which treatment often implies a decrease in reproductive potential. We describe a case of a woman who had a lumbar Ewing’s Sarcoma in 1991, at the age of 8. She was submitted to extended tumourectomy, chemotherapy and local radiotherapy without preservation techniques. In adult life, and after two in vitro fertilization (IVF) reproductive cycles without success, she spontaneously conceived at the age of 32. After an uneventful pregnancy, she delivered a healthy child by caesarean section. This is a rare successful case of a spontaneous and uneventful pregnancy without previous preservation techniques. In the last 30 years, there has been significant development in this area, and currently, there are solutions for these patients, including in prepubertal age.

scholarly journals N-Cadherin Upregulation Promotes the Neurogenic Differentiation of Menstrual Blood-Derived Endometrial Stem Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yanli Liu ◽  
Fen Yang ◽  
Shengying Liang ◽  
Qing Liu ◽  
Sulei Fu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Peripheral Nerve ◽  
Therapeutic Option ◽  
In Vivo Studies ◽  
Menstrual Blood ◽  
Neurogenic Differentiation ◽  
Endometrial Stem Cells ◽  
Medical Disorders

Peripheral nerve injuries are typically caused by either trauma or medical disorders, and recently, stem cell-based therapies have provided a promising treatment approach. Menstrual blood-derived endometrial stem cells (MenSCs) are considered an ideal therapeutic option for peripheral nerve repair due to a noninvasive collection procedure and their high proliferation rate and immunological tolerance. Here, we successfully isolated MenSCs and examined their biological characteristics including their morphology, multipotency, and immunophenotype. Subsequent in vitro studies demonstrated that MenSCs express high levels of neurotrophic factors, such as NT3, NT4, BDNF, and NGF, and are capable of transdifferentiating into glial-like cells under conventional induction conditions. Moreover, upregulation of N-cadherin (N-cad) mRNA and protein expression was observed after neurogenic differentiation. In vivo studies clearly showed that N-cad knockdown via in utero electroporation perturbed the migration and maturation of mouse neural precursor cells (NPCs). Finally, a further transfection assay also confirmed that N-cad upregulation in MenSCs results in the expression of S100. Collectively, our results confirmed the paracrine effect of MenSCs on neuroprotection as well as their potential for transdifferentiation into glial-like cells and demonstrated that N-cad upregulation promotes the neurogenic differentiation of MenSCs, thereby providing support for transgenic MenSC-based therapy for peripheral nerve injury.

scholarly journals In vitro Antibacterial Activity of Organic Extracts of Aloe barbadensis against Multi-drug resistant Pseudomonas aeruginosa Isolated from Wound Specimens

2018 ◽  
Vol 5 ◽  
pp. 69-76
Author(s):  
Mamata Adhikari ◽  
Anil Kumar Sah ◽  
Dev Raj Joshi
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibacterial Activity ◽  
Inhibitory Action ◽  
Therapeutic Option ◽  
Diffusion Method ◽  
Drug Resistant ◽  
Aloe Barbadensis ◽  
Organic Extracts ◽  
In Vitro Antibacterial Activity

Objectives: In order to investigate alternate therapeutic option, this study was carried out to assess the in vitro antibacterial activity of gel extract of Aloe barbadensis against multiple antibiotic resistant Pseudomonas aeruginosa isolated from wound specimens. Methods: A total of 180 different wound specimens collected in a hospital, were subjected to isolate and identify P. aeruginosa by cultural methods. Antibiotic susceptibility testing was done by Kirby- Bauer disc diffusion method to screen multidrug resistant isolates. A. barbadensis extracts were prepared using aqueous and organic solvents and their in vitro inhibitory action was evaluated by agar well diffusion methods. Results: Out of total, 38 (21.1%) of the wound specimens showed the occurrence of P. aeruginosa, among which 15 (39%) isolates were multi-drug resistant. Organic extracts of various concentrations (0.2 - 0.8 v/v %) inhibited 66.7% of MDR and all non-MDR (n = 23) P. aeruginosa with zone of inhibition ranging from 9.5 ±1.0 to 21.3 ± 2.2 mm but not by aqueous extract. A positive Pearson’s correlation (r=0.983) was found between antibacterial effect and concentrations of the extracts. The antibacterial activity of organic extracts was statistically associated with antibiotic resistance profile of the organism (p<0.05). Conclusion: Organic extracts of A. barbadensis revealed variable in vitro inhibitory action against both MDR and non-MDR P. aeruginosa isolated from wound specimens. Although further confirmation is needed, aloe gel extract may be applied as an alternate treatment option.

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