scholarly journals A cell type-selective apoptosis-inducing small molecule for the treatment of brain cancer

2019 ◽  
Vol 116 (13) ◽  
pp. 6435-6440 ◽  
Author(s):  
Natasha C. Lucki ◽  
Genaro R. Villa ◽  
Naja Vergani ◽  
Michael J. Bollong ◽  
Brittney A. Beyer ◽  
...  
Keyword(s):  
Small Molecule ◽  
Brain Cancer ◽  
Critical Role ◽  
Tumor Formation ◽  
Tumor Xenograft ◽  
Drug Candidate ◽  
Cell Type ◽  
Caspase 1 ◽  
A Cell

Glioblastoma multiforme (GBM; grade IV astrocytoma) is the most prevalent and aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation, tumor maintenance, metastasis, drug resistance, and recurrence following surgery. Here we report the identification of a small molecule, termed RIPGBM, from a cell-based chemical screen that selectively induces apoptosis in multiple primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of this compound appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an orthotopic intracranial GBM CSC tumor xenograft mouse model, RIPGBM was found to significantly suppress tumor formation in vivo. Our chemical genetics-based approach has identified a drug candidate and a potential drug target that provide an approach to the development of treatments for this devastating disease.

scholarly journals STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Stephen Skirboll ◽  
Natasha Lucki ◽  
Genaro Villa ◽  
Naja Vergani ◽  
Michael Bollong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Molecules ◽  
Small Molecule ◽  
Large Scale ◽  
Critical Role ◽  
Tumor Formation ◽  
Cell Type ◽  
Caspase 1 ◽  
Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

Abstract 19363: Migration of MicroRNAs From Cardiomyocytes to Cancer Cells Interferes With Tumor Formation in the Adult Heart

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Laura Graciotti ◽  
Toru Hosoda ◽  
Fumihiro Sanada ◽  
Giulia Borghetti ◽  
Christian Arranto ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Critical Role ◽  
Tumor Formation ◽  
Molecular Characteristics ◽  
Cardiac Tumors ◽  
Mcf7 Cells ◽  
Tissue Pressure ◽  
Intramyocardial Injection

The low incidence of cardiac tumors has been attributed to tissue pressure dictated by myocardial mechanics and large coronary blood flow. These variables, however, have failed to consider the possibility that the rare occurrence of heart neoplasms may be dictated by the molecular characteristics of cardiomyocytes. We have shown that miR-1, miR-133a, and miR-499 translocate from myocytes to co-cultured MCF7 breast cancer cells, inhibiting their growth. The transfer of miRs is mediated by gap junction channels and is abolished by Cx43 and Cx45 silencing. Although these in vitro results provided important information on the inhibitory function of miRs in cell proliferation, co-culture of myocytes and cancer cells does not mimic the in vivo organization of the myocardium that allows the formation of multiple sites of coupling between myocytes and tumor cells. To reproduce, at least in part, the in vivo condition, we developed first a physiological model of organ culture. Thick vibratome-cut myocardial slices were placed on a multiwell plate containing an oxygen-saturated sponge. At 24-48 hours, the cultured tissue was viable and myocytes showed a well organized sarcomere structure. Two hours after plating of the organ slices, control MCF7 cells or MCF7 cells in which Cx43 and Cx45 were silenced (MCF7-shCx43-shCx45) were seeded on the myocardium. Control MCF7 cells showed a slower growth rate than MCF7-shCx43-shCx45 cells, a finding consistent with miR translocation and its blockade, respectively. Second, 1 x 106 MCF7 or MCF7 cells overexpressing miR-1, miR-133a, and miR-499 (MCF7-miRs) were injected subcutaneously in NOD-SCID mice; ~45 days later, the tumors developed from MCF7 cells were more than 10-fold larger and 3-fold heavier than those originated from MCF7-miRs cells. Third, these studies were complemented with the intramyocardial injection of 1 x 105 control MCF7 cells. Five weeks later, no neoplastic lesions were identified. However, when an excessive number of MCF7 cells were injected, 1 x 106, tumor formation was apparent. In conclusion, our results indicate that transfer of miR-1, miR-133a, and miR-499 from cardiomyocytes to cancer cells plays a critical role in preventing the generation of tumors in the myocardium.

Gene therapy can target mutations such as BRAF, which have been shown to make tumors more susceptible to autophagy suppression

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Signaling Pathways ◽  
Chemotherapy Resistance ◽  
Effective Strategy ◽  
Cell Type ◽  
Normal Cells ◽  
A Cell ◽  
Cell Type Specific ◽  
Catabolic Process ◽  
Specific Impact

Autophagy is a double-edged sword in cancer, and numerous aspects should be taken into account before deciding on the most effective strategy to target the process. The fact that several clinical studies are now ongoing does not mean that the patient group that may benefit from autophagy-targeting medicines has been identified. Autophagy inhibitors that are more potent and specialized, as well as autophagy indicators, are also desperately required. The fact that these inhibitors only work against tumors that rely on autophagy for survival (RAS mutants) makes it difficult to distinguish them from tumors that continue to develop even when autophagy is absent. Furthermore, mutations such as BRAF have been shown to make tumors more susceptible to autophagy suppression, suggesting that targeting such tumours may be a viable strategy for overcoming their chemotherapy resistance. In the meantime, we are unable to identify if autophagy regulation works in vivo or whether it selectively targets a disease while inflicting injury to other healthy organs and tissues. A cell-type-specific impact appears to be observed with such therapy. As a result, it is just as important to consider the differences between tumors that originate in different organs as it is to consider the signaling pathways that are similar across them. For a therapy or cure to be effective, the proposed intervention must be tailored to the specific needs of each patient.Over the last several years, a growing amount of data has implicated autophagy in a variety of disorders, including cancer. In normal cells, this catabolic process is also required for cell survival and homeostasis. Despite the fact that medications targeting intermediates in the autophagy signaling pathway are being created and evaluated at both the preclinical and clinical levels, given the complicated function of autophagy in cancer, we still have a long way to go in terms of establishing an effective therapeutic approach. This article discusses current tactics for exploiting cancer cells' autophagy dependency, as well as obstacles in the area. We believe that the unanswered concerns raised in this work will stimulate researchers to investigate previously unknown connections between autophagy and other signaling pathways, which might lead to the development of novel, highly specialized autophagy therapies.

scholarly journals Dual Inactivation of RB and p53 Pathways in RAS-Induced Melanomas

2001 ◽  
Vol 21 (6) ◽  
pp. 2144-2153 ◽  
Author(s):  
Nabeel Bardeesy ◽  
Boris C. Bastian ◽  
Aram Hezel ◽  
Dan Pinkel ◽  
Ronald A. DePinho ◽  
...  
Keyword(s):  
Tumor Cells ◽  
P53 Mutation ◽  
Comparative Genomic ◽  
Cell Type ◽  
Specific Expression ◽  
Rb Pathway ◽  
High Incidence ◽  
A Cell ◽  
Cell Type Specific

ABSTRACT The frequent loss of both INK4a and ARF in melanoma raises the question of which INK4a-ARF gene product functions to suppress melanoma genesis in vivo. Moreover, the high incidence of INK4a-ARF inactivation in transformed melanocytes, along with the lack of p53 mutation, implies a cell type-specific role for INK4a-ARF that may not be complemented by other lesions of the RB and p53 pathways. A mouse model of cutaneous melanoma has been generated previously through the combined effects of INK4a Δ2/3 deficiency (null for INK4a and ARF) and melanocyte-specific expression of activated RAS (tyrosinase-driven H-RASV12G, Tyr-RAS). In this study, we made use of this Tyr-RAS allele to determine whether activated RAS can cooperate withp53 loss in melanoma genesis, whether such melanomas are biologically comparable to those arising inINK4a Δ2/3−/− mice, and whether tumor-associated mutations emerge in the p16INK4a-RB pathway in such melanomas. Here, we report that p53inactivation can cooperate with activated RAS to promote the development of cutaneous melanomas that are clinically indistinguishable from those arisen on theINK4a Δ2/3 null background. Genomewide analysis of RAS-induced p53 mutant melanomas by comparative genomic hybridization and candidate gene surveys revealed alterations of key components governing RB-regulated G1/S transition, including c-Myc, cyclin D1, cdc25a, and p21CIP1. Consistent with the profile of c-Myc dysregulation, the reintroduction of p16INK4a profoundly reduced the growth of Tyr-RASINK4a Δ2/3−/− tumor cells but had no effect on tumor cells derived from Tyr-RAS p53 −/−melanomas. Together, these data validate a role for p53inactivation in melanomagenesis and suggest that both the RB and p53 pathways function to suppress melanocyte transformation in vivo in the mouse.

scholarly journals Cophosphorylation of amphiphysin I and dynamin I by Cdk5 regulates clathrin-mediated endocytosis of synaptic vesicles

2003 ◽  
Vol 163 (4) ◽  
pp. 813-824 ◽  
Author(s):  
Kazuhito Tomizawa ◽  
Satoshi Sunada ◽  
Yun-Fei Lu ◽  
Yoshiya Oda ◽  
Masahiro Kinuta ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Critical Role ◽  
Ring Formation ◽  
Free System ◽  
Rich Domain ◽  
A Cell ◽  
Dynamin I ◽  
Deficient Mice

It has been thought that clathrin-mediated endocytosis is regulated by phosphorylation and dephosphorylation of many endocytic proteins, including amphiphysin I and dynamin I. Here, we show that Cdk5/p35-dependent cophosphorylation of amphiphysin I and dynamin I plays a critical role in such processes. Cdk5 inhibitors enhanced the electric stimulation–induced endocytosis in hippocampal neurons, and the endocytosis was also enhanced in the neurons of p35-deficient mice. Cdk5 phosphorylated the proline-rich domain of both amphiphysin I and dynamin I in vitro and in vivo. Cdk5-dependent phosphorylation of amphiphysin I inhibited the association with β-adaptin. Furthermore, the phosphorylation of dynamin I blocked its binding to amphiphysin I. The phosphorylation of each protein reduced the copolymerization into a ring formation in a cell-free system. Moreover, the phosphorylation of both proteins completely disrupted the copolymerization into a ring formation. Finally, phosphorylation of both proteins was undetectable in p35-deficient mice.

scholarly journals Click-xylosides overcome neurotoxic effects of reactive astrocytes and promote neuronal growth in a cell culture model of brain injury

2018 ◽  
Author(s):  
Swarup Vimal ◽  
Balagurunathan Kuberan
Keyword(s):  
Brain Injury ◽  
Hippocampal Neurons ◽  
Critical Role ◽  
Scar Tissue ◽  
Reactive Astrocyte ◽  
Neuronal Growth ◽  
Molecular Approaches ◽  
A Cell ◽  
Excessive Secretion

AbstractAstrocytes, upon activation in response to brain injury, play a critical role in protecting neurons by limiting inflammation through the excessive secretion of many soluble factors, such as, chondroitin sulfate proteoglycans (CSPGs). Unfortunately, excessive CSPGs paradoxically prohibit neuronal recovery and growth, and eventually constitute a scar tissue. Many studies have attempted to overcome this barrier through various molecular approaches including the removal of inhibitory CSPGs by applying chondroitinase enzymes. In this study, we examined whether click-xylosides, which serve as primers of glycosaminoglycan (GAG) biosynthesis, can compete with endogenous inhibitory CSPGs for GAG assembly by serving as decoy molecules and thereby potentially reverse reactive astrocyte mediated neuronal growth inhibition. We investigated the axonal growth of hippocampal neurons in the presence of xyloside treated and untreated reactive astrocyte-conditioned media as a model recapitulating brain injury. Click-xylosides were found to interfere with the GAG biosynthetic machinery in astrocytes and reduced the amount of secreted inhibitory CSPGs by competing with endogenous assembly sites. The extent of underglycosylation was directly related to the outgrowth of hippocampal neurons. Overall, this study suggests that click-xylosides are promising therapeutic agents to treat CNS injuries and warrants further in vivo investigations.

scholarly journals HAIR LOSS AND REGENERATION PERFORMED ON ANIMAL MODELS

2016 ◽  
Vol 89 (3) ◽  
pp. 327-334 ◽  
Author(s):  
Meda Sandra Orasan ◽  
Iulia Ioana Roman ◽  
Andrei Coneac ◽  
Adriana Muresan ◽  
Remus Ioan Orasan
Keyword(s):  
Hair Loss ◽  
Dermal Papilla ◽  
Cell Type ◽  
Advantages And Disadvantages ◽  
A Cell ◽  
Topical Treatments ◽  
Isolated Cell

 Research in the field of reversal hair loss remains a challenging subject.As Minoxidil 2% or 5% and Finasteride are so far the only FDA approved topical treatments for inducing hair regrowth, research is necessary in order to improve therapeutical approach in alopecia. In vitro studies have focused on cultures of a cell type - dermal papilla or organ culture of isolated cell follicles . In vivo research on this topic was performed on mice, rats, hamsters, rabbits, sheep and monkeys, taking into consideration the advantages and disadvantages of each animal model and the depilation options. Further studies are required not only to compare the efficiency of different therapies but more importantly to establish their long term safety.

scholarly journals Catechins and Sialic Acid AttenuateHelicobacter pylori-Triggered Epithelial Caspase-1 Activity and EradicateHelicobacter pyloriInfection

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Jyh-Chin Yang ◽  
Hung-Chih Yang ◽  
Chia-Tung Shun ◽  
Teh-Hong Wang ◽  
Chiang-Ting Chien ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Signaling Pathway ◽  
Immune Cells ◽  
Critical Role ◽  
Gastric Epithelium ◽  
Ags Cells ◽  
Caspase 1 ◽  
H Pylori

The inflammasome/caspase-1 signaling pathway in immune cells plays a critical role in bacterial pathogenesis; however, the regulation of this pathway in the gastric epithelium duringHelicobacter pyloriinfection is yet to be elucidated. Here, we investigated the effect of catechins (CAs), sialic acid (SA), or combination of CA and SA (CASA) onH. pylori-induced caspase-1-mediated epithelial damage, as well asH. pyloricolonizationin vitro(AGS cells) andin vivo(BALB/c mice). Our results indicate that the activity of caspase-1 and the expression of its downstream substrate IL-1βwere upregulated inH. pylori-infected AGS cells. In addition, we observed increased oxidative stress, NADPH oxidase gp91phox, CD68, caspase-1/IL-1β, and apoptosis, but decreased autophagy, in the gastric mucosa ofH. pylori-infected mice. We have further demonstrated that treatment with CASA led to synergistic anti-H. pyloriactivity and was more effective than treatment with CA or SA alone. In particular, treatment with CASA for 10 days eradicatedH. pyloriinfection in up to 95% ofH. pylori-infected mice. Taken together, we suggest that the pathogenesis ofH. pyloriinvolves a gastric epithelial inflammasome/caspase-1 signaling pathway, and our results show that CASA was able to attenuate this pathway and effectively eradicateH. pyloriinfection.

scholarly journals Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Weilin Zhang ◽  
He Ren ◽  
Chunling Xu ◽  
Chongzhuo Zhu ◽  
Hao Wu ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Acute Ischemia ◽  
Dependent Manner ◽  
Genetic Ablation ◽  
A Cell ◽  
Novel Strategy

Mitochondrial dysfunction underlies many prevalent diseases including heart disease arising from acute ischemia/reperfusion (I/R) injury. Here, we demonstrate that mitophagy, which selectively removes damaged or unwanted mitochondria, regulated mitochondrial quality and quantity in vivo. Hypoxia induced extensive mitochondrial degradation in a FUNDC1-dependent manner in platelets, and this was blocked by in vivo administration of a cell-penetrating peptide encompassing the LIR motif of FUNDC1 only in wild-type mice. Genetic ablation of Fundc1 impaired mitochondrial quality and increased mitochondrial mass in platelets and rendered the platelets insensitive to hypoxia and the peptide. Moreover, hypoxic mitophagy in platelets protected the heart from worsening of I/R injury. This represents a new mechanism of the hypoxic preconditioning effect which reduces I/R injury. Our results demonstrate a critical role of mitophagy in mitochondrial quality control and platelet activation, and suggest that manipulation of mitophagy by hypoxia or pharmacological approaches may be a novel strategy for cardioprotection.

scholarly journals Differential requirements of androgen receptor in luminal progenitors during prostate regeneration and tumor initiation

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Chee Wai Chua ◽  
Nusrat J Epsi ◽  
Eva Y Leung ◽  
Shouhong Xuan ◽  
Ming Lei ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Progenitor Cells ◽  
Neuroendocrine Differentiation ◽  
Tumor Formation ◽  
Genetically Engineered ◽  
Cell Of Origin ◽  
Genetically Engineered Mouse Models ◽  
Pten Deletion ◽  
A Cell

Master regulatory genes of tissue specification play key roles in stem/progenitor cells and are often important in cancer. In the prostate, androgen receptor (AR) is a master regulator essential for development and tumorigenesis, but its specific functions in prostate stem/progenitor cells have not been elucidated. We have investigated AR function in CARNs (CAstration-Resistant Nkx3.1-expressing cells), a luminal stem/progenitor cell that functions in prostate regeneration. Using genetically--engineered mouse models and novel prostate epithelial cell lines, we find that progenitor properties of CARNs are largely unaffected by AR deletion, apart from decreased proliferation in vivo. Furthermore, AR loss suppresses tumor formation after deletion of the Pten tumor suppressor in CARNs; however, combined Pten deletion and activation of oncogenic Kras in AR-deleted CARNs result in tumors with focal neuroendocrine differentiation. Our findings show that AR modulates specific progenitor properties of CARNs, including their ability to serve as a cell of origin for prostate cancer.

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