scholarly journals Bcl-XL but Not Bcl-2 Is a Potential Target in Medulloblastoma Therapy

2022 ◽  
Vol 15 (1) ◽  
pp. 91
Author(s):  
Mike-Andrew Westhoff ◽  
Marie Schuler-Ortoli ◽  
Daniela Zerrinius ◽  
Amina Hadzalic ◽  
Andrea Schuster ◽  
...  

Medulloblastoma (MB) is the most common solid tumour in children and, despite current treatment with a rather aggressive combination therapy, accounts for 10% of all deaths associated with paediatric cancer. Breaking the tumour cells’ intrinsic resistance to therapy-induced cell death should lead to less aggressive and more effective treatment options. In other tumour entities, this has been achieved by modulating the balance between the various pro- and anti-apoptotic members of the Bcl-2 family with small molecule inhibitors. To evaluate the therapeutic benefits of ABT-199 (Venetoclax), a Bcl-2 inhibitor, and ABT-263 (Navitoclax), a dual Bcl-XL/Bcl-2 inhibitor, increasingly more relevant model systems were investigated. Starting from established MB cell lines, progressing to primary patient-derived material and finally an experimental tumour system imbedded in an organic environment were chosen. Assessment of the metabolic activity (a surrogate readout for population viability), the induction of DNA fragmentation (apoptosis) and changes in cell number (the combined effect of alterations in proliferation and cell death induction) revealed that ABT-263, but not ABT-199, is a promising candidate for combination therapy, synergizing with cell death-inducing stimuli. Interestingly, in the experimental tumour setting, the sensitizing effect of ABT-263 seems to be predominantly mediated via an anti-proliferative and not a pro-apoptotic effect, opening a future line of investigation. Our data show that modulation of specific members of the Bcl-2 family might be a promising therapeutic addition for the treatment of MB.

2021 ◽  
Vol 8 (6) ◽  
pp. 77
Author(s):  
Oihane Mitxelena-Iribarren ◽  
Sara Lizarbe-Sancha ◽  
Jay Campisi ◽  
Sergio Arana ◽  
Maite Mujika

The use of lipid nanoparticles as biodegradable shells for controlled drug delivery shows promise as a more effective and targeted tumor treatment than traditional treatment methods. Although the combination of target therapy with nanotechnology created new hope for cancer treatment, methodological issues during in vitro validation of nanovehicles slowed their application. In the current work, the effect of methotrexate (MTX) encapsulated in different matrices was evaluated in a dynamic microfluidic platform. Effects on the viability of osteosarcoma cells in the presence of recirculation of cell media, free MTX and two types of blank and drug-containing nanoparticles were successfully assessed in different tumor-mimicking microenvironments. Encapsulated MTX was more effective than the equal dose free drug treatment, as cell death significantly increased under the recirculation of both types of drug-loaded nanoparticles in all concentrations. In fact, MTX-nanoparticles reduced cell population 50 times more than the free drug when 150-µM drug dose was recirculated. Moreover, when compared to the equivalent free drug dose recirculation, cell number was reduced 60 and 100 points more under recirculation of each nanoparticle with a 15-µM drug concentration. Thus, the results obtained with the microfluidic model present MTX-lipid nanoparticles as a promising and more effective therapy for pediatric osteosarcoma treatment than current treatment options.


2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Isabel Weigand ◽  
Jochen Schreiner ◽  
Florian Roehrig ◽  
Na Sun ◽  
Landwehr Laura-Sophie ◽  
...  

Abstract Context: Cell death in the adrenal cortex is ill understood but of high clinical relevance. Resistance of adrenocortical carcinoma (ACC) to current treatment with mitotane and chemotherapy calls for an improved understanding of adrenal cortical cell death processes. Ferroptosis is an iron-dependent form of regulated cell death which is characterized by polyunsaturated lipids adrenic (AdA) and arachidonic acid (AA) peroxidation. Aim: To address the potential role of ferroptosis in the adrenal gland as a potential treatment target of ACC. Methods: Human ACC cells H295R, CU-ACC1 and 2 were used. Protein expression of key enzymes was determined by western blotting. Lipid peroxidation was quantified with BODIPY 581/591 and cell viability with CellTiterGlo after treatment with known inducers and inhibitors of ferroptosis and steroidogenesis, respectively. Results: Adrenocortical tissues are enriched in AdA and AA and express high levels of genes relevant to ferroptosis, such as glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4). Inhibition of GPX4 with RSL3 led to cell death in H295R, CU-ACC1 and 2 cells at EC50 values of 2.4x10-7, 8.1x10-7 and 1.5x10-8 M, respectively. The steroidogenesis inhibitor ketoconazole completely reversed RSL3 cytotoxicity in all three steroidogenic cell lines by reducing lipid peroxidation. Mitotane induced lipid peroxidation but inhibition of ferroptosis with liproxstatin did not protect mitotane-induced cell death. Conclusion: Adrenocortical cells are highly sensitive to ferroptosis due to active steroidogenesis. Triggering this form of cell death could present future novel treatment options against ACC.


Author(s):  
Nadine Huber ◽  
Sonja Korhonen ◽  
Dorit Hoffmann ◽  
Stina Leskelä ◽  
Hannah Rostalski ◽  
...  

AbstractFrontotemporal lobar degeneration (FTLD) comprises a heterogenous group of fatal neurodegenerative diseases and, to date, no validated diagnostic or prognostic biomarkers or effective disease-modifying therapies exist for the different clinical or genetic subtypes of FTLD. Current treatment strategies rely on the off-label use of medications for symptomatic treatment. Changes in several neurotransmitter systems including the glutamatergic, GABAergic, dopaminergic, and serotonergic systems have been reported in FTLD spectrum disease patients. Many FTLD-related clinical and neuropsychiatric symptoms such as aggressive and compulsive behaviour, agitation, as well as altered eating habits and hyperorality can be explained by disturbances in these neurotransmitter systems, suggesting that their targeting might possibly offer new therapeutic options for treating patients with FTLD. This review summarizes the present knowledge on neurotransmitter system deficits and synaptic dysfunction in model systems and patients harbouring the most common genetic causes of FTLD, the hexanucleotide repeat expansion in C9orf72 and mutations in the granulin (GRN) and microtubule-associated protein tau (MAPT) genes. We also describe the current pharmacological treatment options for FLTD that target different neurotransmitter systems.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Ligia I. Bastea ◽  
Laeticia M. A. Hollant ◽  
Heike R. Döppler ◽  
Elizabeth M. Reid ◽  
Peter Storz

Abstract Current treatment options for patients with pancreatic cancer are suboptimal, resulting in a five year survival rate of about 9%. Difficulties with treatment are due to an immunosuppressive, fibrotic tumor microenvironment that prevents drugs from reaching tumor cells, but also to the limited efficacy of existing FDA-approved chemotherapeutic compounds. We here show that the nucleoside analog Sangivamycin and its closely-related compound Toyocamycin target PDA cell lines, and are significantly more efficient than Gemcitabine. Using KINOMEscan screening, we identified the kinase Haspin, which is overexpressed in PDA cell lines and human PDA samples, as a main target for both compounds. Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death. In orthotopically implanted tumors in mice, Sangivamycin was efficient in decreasing the growth of established tumors. In summary, we show that Sangivamycin and derivatives can be an efficient new option for treatment of PDA.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Iñigo Arberas-Jiménez ◽  
Sara García-Davis ◽  
Aitor Rizo-Liendo ◽  
Ines Sifaoui ◽  
María Reyes-Batlle ◽  
...  

Abstract Primary amoebic encephalitis (PAM) is a lethal disease caused by the opportunistic pathogen, Naegleria fowleri. This amoebic species is able to live freely in warm aquatic habitats and to infect children and young adults when they perform risk activities in these water bodies such as swimming or splashing. Besides the need to increase awareness of PAM which will allow an early diagnosis, the development of fully effective therapeutic agents is needed. Current treatment options are amphotericin B and miltefosine which are not fully effective and also present toxicity issues. In this study, the in vitro activity of various sesquiterpenes isolated from the red alga Laurencia johnstonii were tested against the trophozoite stage of a strain of Naegleria fowleri. Moreover, the induced effects (apoptotic cell death) of the most active compound, laurinterol (1), was evaluated by measuring DNA condensation, damages at the mitochondrial level, cell membrane disruption and production of reactive oxygen species (ROS). The obtained results demonstrated that laurinterol was able to eliminate the amoebae at concentrations of 13.42 ± 2.57 µM and also to induced programmed cell death (PCD) in the treated amoebae. Moreover, since ATP levels were highly affected and laurinterol has been previously reported as an inhibitor of the Na+/K+-ATPase sodium–potassium ion pump, comparison with known inhibitors of ATPases were carried out. Our results points out that laurinterol was able to inhibit ENA ATPase pump at concentrations 100 times lower than furosemide.


2012 ◽  
Vol 21 (3) ◽  
pp. 75-84
Author(s):  
Venkata Vijaya K. Dalai ◽  
Jason E. Childress ◽  
Paul E Schulz

Dementia is a major public health concern that afflicts an estimated 24.3 million people worldwide. Great strides are being made in order to better diagnose, prevent, and treat these disorders. Dementia is associated with multiple complications, some of which can be life-threatening, such as dysphagia. There is great variability between dementias in terms of when dysphagia and other swallowing disorders occur. In order to prepare the reader for the other articles in this publication discussing swallowing issues in depth, the authors of this article will provide a brief overview of the prevalence, risk factors, pathogenesis, clinical presentation, diagnosis, current treatment options, and implications for eating for the common forms of neurodegenerative dementias.


2001 ◽  
Vol 13 (4) ◽  
pp. 233-237 ◽  
Author(s):  
Roger Boshes ◽  
Theo Manschreck ◽  
Jean Desrosiers ◽  
Steven Candela ◽  
Meredith Hanrahan-Boshes

2013 ◽  
Vol 3 (3) ◽  
pp. 66 ◽  
Author(s):  
Vanessa Hörmann ◽  
Sivanesan Dhandayuthapani ◽  
James Kumi-Diaka ◽  
Appu Rathinavelu

Background: Prostate cancer is the second most common cancer in American men. The development of alternative preventative and/or treatment options utilizing a combination of phytochemicals and chemotherapeutic drugs could be an attractive alternative compared to conventional carcinoma treatments. Genistein isoflavone is the primary dietary phytochemical found in soy and has demonstrated anti-tumor activities in LNCaP prostate cancer cells. Topotecan Hydrochloride (Hycamtin) is an FDA-approved chemotherapy for secondary treatment of lung, ovarian and cervical cancers. The purpose of this study was to detail the potential activation of the intrinsic apoptotic pathway in LNCaP prostate cancer cells through genistein-topotecan combination treatments. Methods: LNCaP cells were cultured in complete RPMI medium in a monolayer (70-80% confluency) at 37ºC and 5% CO2. Treatment consisted of single and combination groups of genistein and topotecan for 24 hours. The treated cells were assayed for i) growth inhibition through trypan blue exclusion assay and microphotography, ii) classification of cellular death through acridine/ ethidium bromide fluorescent staining, and iii) activation of the intrinsic apoptotic pathway through Jc-1: mitochondrial membrane potential assay, cytochrome c release and Bcl-2 protein expression.Results: The overall data indicated that genistein-topotecan combination was significantly more efficacious in reducing the prostate carcinoma’s viability compared to the single treatment options. In all treatment groups, cell death occurred primarily through the activation of the intrinsic apoptotic pathway.Conclusion: The combination of topotecan and genistein has the potential to lead to treatment options with equal therapeutic efficiency as traditional chemo- and radiation therapies, but lower cell cytotoxicity and fewer side effects in patients. Key words: topotecan; genistein; intrinsic apoptotic cell death


2019 ◽  
Vol 20 (10) ◽  
pp. 1008-1017 ◽  
Author(s):  
Vandita Kakkar ◽  
Manoj Kumar Verma ◽  
Komal Saini ◽  
Indu Pal Kaur

Oral Cancer (OC) is a serious and growing problem which constitutes a huge burden on people in more and less economically developed countries alike. The scenario is clearly depicted from the increase in the expected number of new cases in the US diagnosed with OC from 49,670 people in 2016, to 49,750 cases in 2017. The situation is even more alarming in India, with 75,000 to 80,000 new cases being reported every year, thus making it the OC capital of the world. Leukoplakia, erythroplakia, oral lichen planus, oral submucous fibrosis, discoid lupus erythmatosus, hereditary disorders such as dyskeratosis congenital and epidermolisys bullosa are highlighted by WHO expert working group as the predisposing factors increasing the risk of OC. Consumption of tobacco and alcohol, genetic factors, and human papilloma virus are assigned as the factors contributing to the aetiology of OC. On the other hand, pathogenesis of OC involves not only apoptosis but also pain, inflammation and oxidative stress. Inspite of current treatment options (surgery, radiotherapy, and chemotherapy), OC is often associated with recurrence and formation of secondary primary tumours resulting in poor overall survival rates (∼50%). The intervention of nano technology-based drug delivery systems as therapeutics for cancers is often viewed as a cutting edge for technologists. Though ample literature on the usefulness of nano-coutured cancer therapeutics, rarely any product is in pipeline. Yet, despite all the hype about nanotechnology, there are few ongoing trials. This review discusses the current and future trends of nano-based drug delivery for the treatment of OC.


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