scholarly journals Synergistic Effects of the DRD2/3 Antagonist ONC201 and Radiation in Glioblastoma

2020 ◽  
Author(s):  
Ling He ◽  
Kruttika Bhat ◽  
Angeliki Ioannidis ◽  
Le Zhang ◽  
Nhan T. Nguyen ◽  
...  
Keyword(s):  
Mouse Models ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Therapy Resistance ◽  
List Type ◽  
Current Standard ◽  
Self Renewal ◽  
Glioma Initiating Cells

AbstractBackgroundGlioblastoma (GBM) is the deadliest of all brain cancers in adults. The current standard-of-care is surgery followed by radiotherapy and temozolomide, leading to a median survival time of only 15 months. GBM are organized hierarchically with a small number of glioma-initiating cells, responsible for therapy resistance and tumor recurrence, suggesting that targeting glioma-initiating cells could improve treatment response. ONC201 is a first-in-class anti-tumor agent with clinical efficacy in some forms of high-grade gliomas. Here we test its efficacy against GBM in combination with radiation.MethodsUsing patient-derived GBM lines and mouse models of GBM we test the effects of radiation and ONC201 on GBM self - renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of GBM cells with ONC201 reduced self-renewal, clonogenicity and cell viability in vitro. ONC201 exhibited anti-tumor effects on radioresistant GBM cells indicated by reduced self-renewal in secondary and tertiary glioma spheres. Combined treatment with ONC201 and radiation prolonged survival in syngeneic and patient-derived orthotopic xenograft mouse models of GBM. Subsequent transcriptome analyses after combined treatment revealed shifts in gene expression signatures related to quiescent GBM populations, GBM plasticity, and GBM stem cells.ConclusionsOur findings suggest that combined treatment with the DRD2/3 antagonist ONC201 and radiation improves the efficacy of radiation against GBM in vitro and in vivo through suppression of GICs without increasing toxicity in mouse models of GBM. A clinical assessment of this novel combination therapy against GBM is further warranted.Key points- Combined treatment of ONC201 and radiation exhibit anti-tumor effects on cells from primary and recurrent GBM- Combined treatment significantly prolongs survival in vivo- Combined treatment potentially targets the quiescent GBM cell populationImportance of the StudyThe survival rates for patients with GBM are unacceptably low and novel treatment approaches are needed. This study provides evidence that a combination of radiation and the dopamine receptor antagonist ONC201 significantly prolongs survival in mouse models of glioma.

scholarly journals LARP7 is a BRCA1 ubiquitinase substrate and regulates genome stability and tumorigenesis

2019 ◽  
Author(s):  
Fang Zhang ◽  
Pengyi Yan ◽  
Huijing Yu ◽  
Huangying Le ◽  
Zixuan li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Rna Binding ◽  
Tumor Therapy ◽  
Genotoxic Stress ◽  
Therapy Resistance ◽  
List Type ◽  
M Cell

SummaryAttenuated DNA repair leads to genomic instability and tumorigenesis. BRCA1/BARD1 are the best known tumor suppressors that promote homology recombination (HR) and arrest cell cycle at G2/M checkpoint. As E3 ubiquitin ligases, their ubiquitinase activity has been known to involve in the HR and tumor suppression, but the mechanism remains ambiguous. Here, we demonstrated upon genotoxic stress, BRCA1 together with BARD1 catalyzed the K48 ployubiquitination on LARP7, a 7SK RNA binding protein known to control RNAPII pausing, and thereby degraded it through 26S ubiquitin-proteasome pathway. Depleting LARP7 suppressed the expression of CDK1 complex, arrested cell at G2/M DNA damage checkpoint and reduced BRCA2 phosphorylation which thereby facilitated RAD51 recruitment to damaged DNA to enhance HR. Importantly, LARP7 depletion observed in breast patients lead to the chemoradiotherapy resistance both in vitro and in vivo. Together, this study unveils a mechanism by which BRCA1/BARD1 utilizes their E3 ligase activity to control HR and cell cycle, and highlights LARP7 as a potential target for cancer prevention and therapy.HighlightsDNA damage response downregulates LARP7 through BRCA1/BARD1BRCA1/BARD1 catalyzes the K48 polyubiquitination on LARP7LARP7 promotes G2/M cell cycle transition and tumorigenesis via CDK1 complexLARP7 disputes homology-directed repair that leads to tumor therapy resistance

scholarly journals Imaging Metformin Efficacy as Add-On Therapy in Cells and Mouse Models of Human EGFR Glioblastoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Silvia Valtorta ◽  
Alessia Lo Dico ◽  
Isabella Raccagni ◽  
Cristina Martelli ◽  
Valentina Pieri ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mouse Models ◽  
Molecular Subtype ◽  
Combined Treatment ◽  
Response To Therapy ◽  
Translocator Protein ◽  
Common Mechanism ◽  
Duration Of Treatment

Glioblastoma (GBM) is a highly aggressive tumor of the brain. Despite the efforts, response to current therapies is poor and 2-years survival rate ranging from 6-12%. Here, we evaluated the preclinical efficacy of Metformin (MET) as add-on therapy to Temozolomide (TMZ) and the ability of [18F]FLT (activity of thymidine kinase 1 related to cell proliferation) and [18F]VC701 (translocator protein, TSPO) Positron Emission Tomography (PET) radiotracers to predict tumor response to therapy. Indeed, TSPO is expressed on the outer mitochondrial membrane of activated microglia/macrophages, tumor cells, astrocytes and endothelial cells. TMZ-sensitive (Gli36ΔEGFR-1 and L0627) or -resistant (Gli36ΔEGFR-2) GBM cell lines representative of classical molecular subtype were tested in vitro and in vivo in orthotopic mouse models. Our results indicate that in vitro, MET increased the efficacy of TMZ on TMZ-sensitive and on TMZ-resistant cells by deregulating the balance between pro-survival (bcl2) and pro-apoptotic (bax/bad) Bcl-family members and promoting early apoptosis in both Gli36ΔEGFR-1 and Gli36ΔEGFR-2 cells. In vivo, MET add-on significantly extended the median survival of tumor-bearing mice compared to TMZ-treated ones and reduced the rate of recurrence in the TMZ-sensitive models. PET studies with the cell proliferation radiopharmaceutical [18F]FLT performed at early time during treatment were able to distinguish responder from non-responder to TMZ but not to predict the duration of the effect. On the contrary, [18F]VC701 uptake was reduced only in mice treated with MET plus TMZ and levels of uptake negatively correlated with animals’ survival. Overall, our data showed that MET addition improved TMZ efficacy in GBM preclinical models representative of classical molecular subtype increasing survival time and reducing tumor relapsing rate. Finally, results from PET imaging suggest that the reduction of cell proliferation represents a common mechanism of TMZ and combined treatment, whereas only the last was able to reduce TSPO. This reduction was associated with the duration of treatment response. TSPO-ligand may be used as a complementary molecular imaging marker to predict tumor microenvironment related treatment effects.

scholarly journals Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

2020 ◽  
Author(s):  
Mohammad Saki ◽  
Kruttika Bhat ◽  
Fei Cheng ◽  
Ling He ◽  
Le Zhang ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Dopamine Receptor ◽  
Mouse Models ◽  
Cholesterol Biosynthesis ◽  
Combined Treatment ◽  
Unmet Need ◽  
Survival Times ◽  
Self Renewal ◽  
Dopamine Receptor Antagonist

AbstractBackgroundGlioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options.MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals.ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

scholarly journals KRAS-mutant colon cancer cells respond to combined treatment of ABT263 and axitinib

2019 ◽  
Vol 39 (3) ◽  
Author(s):  
Guihua Wang ◽  
Ying Huang ◽  
Zhipeng Wu ◽  
Chunmei Zhao ◽  
Hui Cong ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Small Molecules ◽  
Cancer Cells ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Colon Cancer Cells ◽  
Oncogene Addiction ◽  
In Vivo Growth

Abstract Significant challenges to develop selective and effective pharmacological inhibitors for important oncoproteins like RAS continue impeding the success to treat cancers driven by such mutations. In the present study, the ABT263 and axitinib combination imposed synergistic effects on RAS-mutant colon cancer cells. The combination inhibited in vitro and in vivo growth of the cancer cells by enhancing apoptosis. Furthermore, AKT and Wnt/β-catenin signaling pathways were slightly down-regulated by the combination in KRAS-mutant colon cancer cells. The current results indicate that oncogene addiction can be targeted for therapy in colon cancer cells harboring the RAS-mutant. Therefore, targeting oncogene addiction can be a viable strategy for treating refractory cancers driven by important oncogenes, such as KRAS, which are otherwise difficult to be targeted by small molecules.

scholarly journals Combined Targeting of AKT and mTOR Inhibits Proliferation of Human NF1-Associated Malignant Peripheral Nerve Sheath Tumour Cells In Vitro but not in a Xenograft Mouse Model In Vivo

2020 ◽  
Vol 21 (4) ◽  
pp. 1548
Author(s):  
Alexander Schulte ◽  
Florian Ewald ◽  
Melanie Spyra ◽  
Daniel J. Smit ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Peripheral Nerve ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Mtor Inhibition ◽  
Nerve Sheath

Persistent signalling via the PI3K/AKT/mTOR pathway is a major driver of malignancy in NF1-associated malignant peripheral nerve sheath tumours (MPNST). Nevertheless, single targeting of this pathway is not sufficient to inhibit MPNST growth. In this report, we demonstrate that combined treatment with the allosteric pan-AKT inhibitor MK-2206 and the mTORC1/mTORC2 inhibitor AZD8055 has synergistic effects on the viability of MPNST cell lines in comparison to the treatment with each compound alone. However, when treating animals bearing experimental MPNST with the combined AKT/mTOR regime, no influence on tumour growth was observed. Further analysis of the MPNST xenograft tumours resistant to AKT/mTOR treatment revealed a reactivation of both AKT and mTOR in several tumour samples. Additional targeting of the RAS/RAF/MEK/MAPK pathway with the allosteric MEK1/2 inhibitor AZD6244 showed synergistic effects on the viability of MPNST cell lines in vitro in comparison to the dual AKT/mTOR inhibition. In summary, these data indicate that combined treatment with AKT and mTOR inhibitors is effective on MPNST cells in vitro but tumour resistance can occur rapidly in vivo by restoration of AKT/mTOR signalling. Our data further suggest that a triple treatment with inhibitors against AKT, mTORC1/2 and MEK1/2 may be a promising treatment option that should be further analysed in an experimental MPNST mouse model in vivo.

scholarly journals Sox2 modulation increases naïve pluripotency plasticity

2020 ◽  
Author(s):  
Kathryn Tremble ◽  
Giuliano G. Stirparo ◽  
Lawrence E. Bates ◽  
Katsiaryna Maskalenka ◽  
Hannah T. Stuart ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Signature ◽  
Regulatory Sequences ◽  
List Type ◽  
Self Renewal ◽  
Developmental Potential ◽  
Sox2 Expression ◽  
Induced Pluripotency

AbstractInduced pluripotency provides a tool to explore the molecular mechanisms underlying the establishment, maintenance and differentiation of naïve pluripotent stem cells (nPSCs). Here, we report that self-renewal of nPSCs requires minimal Sox2 expression (Sox2-low). Sox2-low nPSCs do not show impaired neuroectoderm specification and differentiate efficiently in vitro into all embryonic germ lineages. Strikingly, Sox2-low cells also differentiate towards the trophoblast lineage both in vitro and in vivo. At the single-cell level self-renewing Sox2-low nPSCs exhibit a homogeneous naïve molecular signature. However, they also display a basal trophoblast molecular signature and decreased ability of Oct4 to bind naïve-associated regulatory sequences compared to control cells. These features underlie observed enhanced cell potency upon the removal of self-renewing cues. In sum, this work defines Sox2 as a restrictor of developmental potential and suggests perturbation of the naïve pluripotent network as an underlying cause of increased cell potency.HighlightsLow Sox2 expression is sufficient for naïve pluripotent stem cell self-renewalLow Sox2 expression does not impair neurectoderm differentiation in vitroLow Sox2 expression impairs Oct4 genomic occupancyLow Sox2 expression increases naïve pluripotent cell plasticity in vitro and in vivo

scholarly journals The Synergistic Effects of Pyrotinib Combined With Adriamycin on HER2-Positive Breast Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Chaokun Wang ◽  
Shuzhen Deng ◽  
Jing Chen ◽  
Xiangyun Xu ◽  
Xiaochen Hu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Synergistic Effects ◽  
Combined Treatment ◽  
Phase Cell ◽  
Migration And Invasion ◽  
Combination Group ◽  
Phase Arrest ◽  
G2 Phase

Pyrotinib (PYR) is a pan-HER kinase inhibitor that inhibits signaling via the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. In this study, we aimed to investigate the antitumor efficacy of pyrotinib combined with adriamycin (ADM) and explore its mechanisms on HER2+ breast cancer. We investigated the effects of PYR and ADM on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of PYR, ADM or PYR combined with ADM on cell proliferation, migration, and invasion of SK-BR-3 and AU565 cells in vitro. Cell apoptosis and cycle were detected through flow cytometry. In vivo, xenograft models were established to test the effect of PYR, ADM, or the combined therapy on the nude mice. Western blotting was performed to assess the expression of Akt, p-Akt, p-65, p-p65, and FOXC1. The results indicated that PYR and ADM significantly inhibited the proliferation, migration, and invasion of SK-BR-3 and AU565 cells, and the inhibitory rate of the combination group was higher than each monotherapy group. PYR induced G1 phase cell-cycle arrest, while ADM induced G2 phase arrest, while the combination group induced G2 phase arrest. The combined treatment showed synergistic anticancer activities. Moreover, PYR significantly downregulated the expression of p-Akt, p-p65, and FOXC1. In clinical settings, PYR also exerts satisfactory efficacy against breast cancer. These findings suggest that the combination of PYR and ADM shows synergistic effects both in vitro and in vivo. PYR suppresses the proliferation, migration, and invasion of breast cancers through down-regulation of the Akt/p65/FOXC1 pathway.

scholarly journals Dopamine Receptor Antagonists, Radiation, and Cholesterol Biosynthesis in Mouse Models of Glioblastoma

2021 ◽  
Author(s):  
Kruttika Bhat ◽  
Mohammad Saki ◽  
Fei Cheng ◽  
Ling He ◽  
Le Zhang ◽  
...  
Keyword(s):  
Dopamine Receptor ◽  
Mouse Models ◽  
Cholesterol Biosynthesis ◽  
Combined Treatment ◽  
Resistance Mechanism ◽  
Rank Test ◽  
Self Renewal ◽  
Dopamine Receptor Antagonist ◽  
Log Rank Test

Abstract Background Glioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options. Methods Using patient-derived HK-157, HK-308, HK-374, and HK-382 glioblastoma lines, the GL261 orthotopic mouse models of glioblastoma and HK-374 patient-derived orthotopic xenografts we tested the effect of radiation and the dopamine receptor antagonist quetiapine on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism was investigated using RNA-Sequencing. The blood-brain-barrier-penetrating statin atorvastatin was used to overcome this resistance mechanism. All statistical tests were 2-sided. Results Treatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing mice. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered GL261 and HK-374 orthotopic tumors vulnerable to simultaneous treatment with atorvastatin and further statistically significantly prolonged the survival of C57BL/6 (n = 10 to 16 mice per group; median survival not reached; Log-Rank test, p < 0.001) and NSG mice (n = 8 to 21 mice per group; hazard ratio = 3.96, 95% confidence interval = 0.29 to 12.40; Log-Rank test, p < 0.001), respectively. Conclusions Our results indicate promising therapeutic efficacy with the triple combination of quetiapine, atorvastatin and radiation treatment against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

LACK OF EFFECT OF CORTICOSTEROIDS ON THE IN VIVO DISAPPEARANCE OF SULFHYDRYL-INHIBITED AND ANTIBODY-COATED ERYTHROCYTES

1964 ◽  
Vol 47 (3_Suppl) ◽  
pp. S28-S36
Author(s):  
Kailash N. Agarwal
Keyword(s):  
Red Cells ◽  
List Type ◽  
Red Cell

ABSTRACT Red cells were incubated in vitro with sulfhydryl inhibitors and Rhantibody with and without prior incubation with prednisolone-hemisuccinate. These erythrocytes were labelled with Cr51 and P32 and their disappearance in vivo after autotransfusion was measured. Prior incubation with prednisolone-hemisuccinate had no effect on the rate of red cell disappearance. The disappearance of the cells was shown to take place without appreciable intravascular destruction.

Recent Patents on Anti-Cancer Potential of Helenalin

2020 ◽  
Vol 15 (2) ◽  
pp. 132-142
Author(s):  
Priyanka Kriplani ◽  
Kumar Guarve
Keyword(s):  
Synergistic Effects ◽  
Therapeutic Interventions ◽  
Active Constituent ◽  
Scientific Impact ◽  
Isolation Techniques ◽  
Anti Cancer ◽  
Prevention Of Cancer ◽  
Synthetic Derivatives

Background: Arnica montana, containing helenalin as its principal active constituent, is the most widely used plant to treat various ailments. Recent studies indicate that Arnica and helenalin provide significant health benefits, including anti-inflammatory, neuroprotective, antioxidant, cholesterol-lowering, immunomodulatory, and most important, anti-cancer properties. Objective: The objective of the present study is to overview the recent patents of Arnica and its principal constituent helenalin, including new methods of isolation, and their use in the prevention of cancer and other ailments. Methods: Current prose and patents emphasizing the anti-cancer potential of helenalin and Arnica, incorporated as anti-inflammary agents in anti-cancer preparations, have been identified and reviewed with particular emphasis on their scientific impact and novelty. Results: Helenalin has shown its anti-cancer potential to treat multiple types of tumors, both in vitro and in vivo. It has also portrayed synergistic effects when given in combination with other anti- cancer drugs or natural compounds. New purification/isolation techniques are also developing with novel helenalin formulations and its synthetic derivatives have been developed to increase its solubility and bioavailability. Conclusion: The promising anti-cancer potential of helenalin in various preclinical studies may open new avenues for therapeutic interventions in different tumors. Thus clinical trials validating its tumor suppressing and chemopreventive activities, particularly in conjunction with standard therapies, are immediately required.

Sign in / Sign up

Export Citation Format

Share Document