The growing cost of medical care worldwide, particularly in oncology, has incentivized researchers and physicians to repurpose clinically used drugs to alleviate the financial burden of drug ...development and offer potential new therapeutics. Recent works have demonstrated anticancer properties of the FDA-approved drug ribavirin, a synthetic guanosine analogue and antiviral molecule used over the past four decades for the treatment of hepatitis C. The efficacy of ribavirin in cancer has been explored through several preclinical models and ongoing clinical trials in multiple cancers, including acute myeloid leukemia, oropharyngeal squamous cell carcinoma, and metastatic breast cancer. In this review, we summarize the role of ribavirin as an antiviral medication and focus our attention on its recent use as an antitumoral agent. We highlight current knowledge of the potential use and mechanisms of action of ribavirin in cancer. Because current therapeutics for patients with cancer still fail to cure, introducing new forms of treatment is essential. Converging evidence suggests that ribavirin represents a promising addition to a generation of newly repurposed safe and effective anticancer agents.
Display omitted
Glioblastomas have been historically difficult to treat with poor long-term survival. With novel strategies focused on targeting hypoxia-inducible factor (HIF) regulatory pathways, ...recent evidence has shown that Acriflavine (ACF) can effectively target glioma invasiveness and recurrence. However, local delivery of ACF and its combinatory effects with Temozolomide (TMZ) and radiation therapy (XRT) have not yet been optimized. In this study we test a novel polymeric matrix that can gradually release ACF at the tumor bed site in combination with systemic TMZ and XRT. In vitro cytotoxicity assays of ACF in combination with TMZ and XRT were performed on rodent and human cell lines with CCK-8 and flow cytometry. In vitro drug release was measured and intracranial safety was assessed in tumor-free animals. Finally, efficacy was assessed in an intracranial gliosarcoma model and combination therapy with TMZ and XRT evaluated. Combination therapy of ACF, TMZ, and XRT was able to reduce cell viability and induce apoptosis in glioma cells. In vitro and in vivo release of ACF was measured in benchtop and animal models. Efficacy was established in an in vivo gliosarcoma model in which intracranial ACF (p < 0.01) significantly improved median survival and the combination therapy of ACF, TMZ and XRT (p < 0.01) significantly improved median survival and led to long-term survival (LTS). We provide evidence that ACF, combined with TMZ and XRT, led to LTS in an intracranial model of rat gliosarcoma. These findings, in combination with the use of a novel polymeric matrix that allows more gradual drug delivery, constitute a first step in the translation of this novel strategy to human use.
Abstract
Nasopharyngeal carcinoma (NPC) is a squamous cell carcinoma with a proclivity for systemic dissemination, leading many patients to present with advanced stage disease and fail available ...treatments. There is a notable lack of targeted therapies for NPC, despite working knowledge of multiple proteins with integral roles in NPC cancer biology. These proteins include EZH2, Snail, eIF4E, and IMPDH, which are all overexpressed in NPC and correlated with poor prognosis. These proteins are known to be modulated by ribavirin, an FDA-approved hepatitis C antiviral that has recently been repurposed as a promising therapeutic in several solid and hematologic malignancies. Here, we investigated the potential of ribavirin as a targeted anticancer agent in five human NPC cell lines. Using cellular growth assays, flow cytometry, BrdU cell proliferation assays, scratch wound assays, and invasion assays, we show in vitro that ribavirin decreases NPC cellular proliferation, migration, and invasion and promotes cell-cycle arrest and cell death. Modulation of EZH2, Snail, eIF4E, IMPDH, mTOR, and cyclin D1 were observed in Western blots and enzymatic activity assays in response to ribavirin treatment. As monotherapy, ribavirin reduced flank tumor growth in multiple NPC xenograft models in vivo. Most importantly, we demonstrate that ribavirin enhanced the effects of radiotherapy, a central component of NPC treatment, both in vitro and in vivo. Our work suggests that NPC responds to ribavirin-mediated EZH2, Snail, eIF4E, IMPDH, and mTOR changes and positions ribavirin for clinical evaluation as a potential addition to our NPC treatment armamentarium.
Abstract
BACKGROUND
Hydrocephalus is managed by surgically implanting flow-diversion technologies such as differential pressure valves and antisiphoning devices; however, such hardware is prone to ...failure. Extensive research has tested them in flow-controlled settings using saline or de-aerated water, yet little has been done to validate their performance in a setting recreating physiologically relevant parameters, including intracranial pressures, cerebrospinal fluid (CSF) protein content, and body position.
OBJECTIVE
To more accurately chart the episodic drainage characteristics of flow-diversion technology. A gravity-driven benchtop model of flow was designed and tested continuously during weeks-long trials.
METHODS
Using a hydrostatic pressure gradient as the sole driving force, interval flow rates of 6 valves were examined in parallel with various fluids. Daily trials in the upright and supine positions were run with fluid output collected from distal catheters placed at alternating heights for extended intervals.
RESULTS
Significant variability in flow rates was observed, both within specific individual valves across different trials and among multiple valves of the same type. These intervalve and intravalve variabilities were greatest during supine trials and with increased protein. None of the valves showed evidence of overt obstruction during 30 d of exposure to CSF containing 5 g/L protein.
CONCLUSION
Day-to-day variability of ball-in-cone differential pressure shunt valves may increase overdrainage risk. Narrow-lumen high-resistance flow control devices as tested here under similar conditions appear to achieve more consistent flow rates, suggesting their use may be advantageous, and did not demonstrate any blockage or trend of decreasing flow over the 3 wk of chronic use.
Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E ...(eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma.
Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells.
Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004).
The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.
Deregulation of mRNA translation is a widespread characteristic of glioblastoma (GBM), aggressive malignant brain tumors that are resistant to conventional therapies. RNA-binding proteins (RBPs) play ...a critical role in translational regulation, yet the mechanisms and impact of these regulations on cancer development, progression and response to therapy remain to be fully understood. Here, we showed that hnRNP H/F RBPs are potent regulators of translation through several mechanisms that converge to modulate the expression and/or the activity of translation initiation factors. Among these, hnRNP H/F regulate the phosphorylation of eIF4E and its translational targets by controlling RNA splicing of the
kinase mRNA, which in turn modulates the MEK-ERK/MAPK signaling pathway. The underlying mechanism involves RNA G-quadruplex (RG4s), RNA structures whose modulation phenocopies hnRNP H/F translation regulation in GBM cells. Our results highlighted that hnRNP H/F are essential for key functional pathways regulating proliferation and survival of GBM, highlighting its targeting as a promising strategy for improving therapeutic outcomes.
Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a ...subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.
Medulloblastoma (MB) is the most common brain malignancy in children, and is still responsible for significant mortality and morbidity. The aim of this study was to assess the safety and efficacy of ...Disulfiram (DSF), an FDA-approved inhibitor of Aldehyde-Dehydrogenase (ALDH), and Copper (Cu++) in human SSH-driven and Group 3 MB. The molecular mechanisms, effect on cancer-stem-cells (CSC) and DNA damage were investigated in xenograft models.
The cytotoxic and anti-CSC effects of DSF/Cu++ were evaluated with clonogenic assays, flow-cytometry, immunofluorescence, western-blotting. ONS76, UW228 (SHH-driven with Tp53m), D425med, D283 and D341 (Group 3) cell-lines were used. In vivo survival and nuclear protein localization protein-4 (NPL4), Ki67, Cleaved-Caspase-3, GFAP and NeuN expression were assessed in two Group 3 MB xenografts with immunohistochemistry and western-blotting.
Significant in vitro cytotoxicity was demonstrated at nanomolar concentrations. DSF/Cu++ induced cell-death through NPL4 accumulation in cell-nucleus and buildup of poly-ubiquitylated proteins. Flow-cytometry demonstrated a significant decrease in ALDH+, Nestin+ and CD133+ following treatment, anti-CSC effect was confirmed in vitro and in vivo. DSF/Cu++ prolonged survival, and increased nuclear NPL4 expression in vivo.
Our data suggest that this combination may serve as a novel treatment, as monotherapy or in combination with existing therapies, for aggressive subtypes of pediatric MB.
Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive, malignant tumors and are the most common malignant brain tumor in children under 6 months of age. Currently, there is no standard ...treatment for AT/RT. Recent studies have reported potential anti-tumoral properties of ribavirin, a guanosine analog and anti-viral molecule approved by the Food and Drug Administration for treatment of hepatitis C. We previously demonstrated that ribavirin inhibited glioma cell growth
and
. Based on these results and the fact that no pre-clinical model of ribavirin in AT/RT exists, we decided to investigate the effect of ribavirin on several human AT/RT cell lines (BT12, BT16, and BT37) both
and
. We provide evidence that ribavirin has a significant impact on AT/RT cell growth and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E and/or EZH2 pathways. Interestingly, using scratch wound and transwell Boyden chamber assays, we observed that ribavirin also impairs AT/RT cell migration, invasion, and adhesion. Finally, we demonstrate that ribavirin significantly improves the survival of mice orthotopically implanted with BT12 cells. Our work establishes that ribavirin is effective against AT/RT by decreasing tumoral cell growth and dissemination and could represent a new therapeutic option for children with this deadly disease.
Paroxysmal dysarthria and ataxia (PDA) is a rare syndrome characterized by brief, stereotyped episodes of slurred speech, clumsiness with extremities, or vertigo. It is usually observed in young ...patients suffering from multiple sclerosis with numerous lesions. PDA is challenging to identify in those presenting with atypical patterns. Here, a non-ataxic variant of PDA in an otherwise neurologically healthy elderly man is presented who had a single midbrain lesion. A broad diagnostic workup illustrates the challenges of identifying PDA. Teaching points emphasize the significance of the midbrain lesion and response to anti-epileptic medication.
•Paroxysmal Dysarthria and Ataxia (PDA) is a very rare MS-related paroxysm•Case of a non-ataxic PDA variant in an otherwise neurologically healthy elderly man•Video clearly shows the symptoms of this Spontaneous Paroxysmal Dysarthria•Solitary midbrain lesions and responsiveness to anti-epileptics are key features
PDF
