scholarly journals Triple Combination Nitazoxanide, Ribavirin, and Hydroxychloroquine results in the multiplicative reduction of in vitro SARS-CoV-2 viral replication

2020 ◽  
Author(s):  
Elena Lian ◽  
Carley McAlister ◽  
Gabriela Ramirez ◽  
David N. Chernoff ◽  
Gregory Went ◽  
...  
Keyword(s):  
Viral Replication ◽  
Low Cost ◽  
Virus Yield ◽  
Triple Combination ◽  
Triple Combination Therapy ◽  
Time To Peak ◽  
Log Reduction ◽  
Additional Cell ◽  
Approved Drugs

AbstractBackgroundAn immediate unmet medical need exists to test and develop existing approved drugs against SARS-COV-2. Despite many efforts, very little progress has been made regarding finding low-cost oral medicines that can be made widely available worldwide to address the global pandemic.MethodsWe sought to examine if a triple combination of nitazoxanide (using its active metabolite tizoxanide), ribavirin, and hydroxychloroquine would lead to a multiplicative effects on viral replication of SARS-COV-2 resulting in a significant reduction of virus yield using VERO E6 cells as a model of viral replication.ResultsVirus yield measured in PFU/ml was ~ 2 logs lower with triple combination versus either drug alone, resulting in the prolongation of time to peak cytopathic effects (CPE). The time to produce 50% CPE increased from 2.8 days for viral controls versus 5.3 days for triple combination therapy. Finally, for each 1-log reduction in virus yield 24 hours post-infection, there was an additional 0.7-day delay in onset of CPE.ConclusionsA triple combination of tizoxanide, ribavirin, and hydroxychloroquine produced a reduction in SARS-COV-2 viral replication in Vero E6 cells, warranting exploration in additional cell lines as well as human clinical trials.

scholarly journals Repurposing inhibitors for SARS-CoV2 main protease

2020 ◽  
Author(s):  
Kumar Sharp
Keyword(s):  
Viral Replication ◽  
Active Sites ◽  
Drug Repurposing ◽  
Chemotherapeutic Drugs ◽  
Short Term ◽  
Main Protease ◽  
Potential Binding ◽  
Approved Drugs ◽  
Fda Approved Drugs

Abstract SARS-CoV2 main protease is important for viral replication and one of the most potential targets for drug development in this current pandemic. Drug repurposing is a promising field to provide potential short-term acceptable therapy for management of coronavirus till a specific anti-viral for coronavirus is developed. In-silico drug repurposing screening is the current fastest way to repurpose drugs by targeting active sites in fraction of seconds. In this study, SARS-CoV2 main protease is being targeted by 1050 FDA-approved drugs to inhibit its activity thereby interfering with viral replication. Chemotherapeutic drugs and anti-retroviral drugs have shown potential binding as inhibitor. In-vitro and clinical trials required to establish final fact.

scholarly journals Targeting the COX2/MET/TOPK signaling axis induces apoptosis in gefitinib-resistant NSCLC cells

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Juanjuan Xiao ◽  
Fei Wang ◽  
Hui Lu ◽  
Sanpeng Xu ◽  
Ling Zou ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Ex Vivo ◽  
Low Cost ◽  
Progression Free Survival ◽  
Signaling Axis ◽  
Approved Drugs ◽  
Gefitinib Resistance ◽  
Resistant Cells

Abstract MET overactivation is one of the crucial reasons for tyrosine kinase inhibitor (TKI) resistance, but the mechanisms are not wholly clear. Here, COX2, TOPK, and MET expression were examined in EGFR-activating mutated NSCLC by immunohistochemical (IHC) analysis. The relationship between COX2, TOPK, and MET was explored in vitro and ex vivo. In addition, the inhibition of HCC827GR cell growth by combining COX2 inhibitor (celecoxib), TOPK inhibitor (pantoprazole), and gefitinib was verified ex vivo and in vivo. We found that COX2 and TOPK were highly expressed in EGFR-activating mutated NSCLC and the progression-free survival (PFS) of triple-positive (COX2, MET, and TOPK) patients was shorter than that of triple-negative patients. Then, we observed that the COX2-TXA2 signaling pathway modulated MET through AP-1, resulting in an inhibition of apoptosis in gefitinib-resistant cells. Moreover, we demonstrated that MET could phosphorylate TOPK at Tyr74 and then prevent apoptosis in gefitinib-resistant cells. In line with these findings, the combination of celecoxib, pantoprazole, and gefitinib could induce apoptosis in gefitinib-resistant cells and inhibit tumor growth ex vivo and in vivo. Our work reveals a novel COX2/MET/TOPK signaling axis that can prevent apoptosis in gefitinib-resistant cells and suggests that a triple combination of FDA-approved drugs would provide a low-cost and practical strategy to overcome gefitinib resistance.

scholarly journals The Benefit of Reactivating p53 under MAPK Inhibition on the Efficacy of Radiotherapy in Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1093 ◽  
Author(s):  
Mohammad Krayem ◽  
Malak Sabbah ◽  
Ahmad Najem ◽  
An Wouters ◽  
Filip Lardon ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Primary Melanoma ◽  
Melanoma Cells ◽  
Tumor Growth Inhibition ◽  
Triple Combination ◽  
Complete Excision ◽  
Triple Combination Therapy ◽  
P53 Expression ◽  
P53 Reactivation

Radiotherapy (RT) in patients with melanoma historically showed suboptimal results, because the disease is often radioresistant due to various mechanisms such as scavenging free radicals by thiols, pigmentary machinery, or enhanced DNA repair. However, radiotherapy has been utilized as adjuvant therapy after the complete excision of primary melanoma and lymph nodes to reduce the rate of nodal recurrences in high-risk patients. The resistance of melanoma cells to radiotherapy may also be in relation with the constitutive activation of the MAPK pathway and/or with the inactivation of p53 observed in about 90% of melanomas. In this study, we aimed to assess the potential benefit of adding RT to BRAF-mutated melanoma cells under a combined p53 reactivation and MAPK inhibition in vitro and in a preclinical animal model. We found that the combination of BRAF inhibition (vemurafenib, which completely shuts down the MAPK pathway), together with p53 reactivation (PRIMA-1Met) significantly enhanced the radiosensitivity of BRAF-mutant melanoma cells. This was accompanied by an increase in both p53 expression and activity. Of note, we found that radiation alone markedly promoted both ERK and AKT phosphorylation, thus contributing to radioresistance. The combination of vemurafenib and PRIMA-1Met caused the inactivation of both MAPK kinase and PI3K/AKT pathways. Furthermore, when combined with radiotherapy, it was able to significantly enhance melanoma cell radiosensitivity. Interestingly, in nude mice bearing melanoma xenografts, the latter triple combination had not only a synergistic effect on tumor growth inhibition, but also a potent control on tumor regrowth in all animals after finishing the triple combination therapy. RT alone had only a weak effect. In conclusion, we provide a basis for a strategy that may overcome the radioresistance of BRAF-mutated melanoma cells to radiotherapy. Whether this will translate into a rational to use radiotherapy in the curative setting in BRAF-mutated melanoma patients deserves consideration.

EXTH-41. IMPROVING THE RADIOSENSITIVITY OF DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG) BY TARGETING HYPOXIA AND MITOCHONDRIAL METABOLISM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi172-vi172
Author(s):  
Han Shen ◽  
Cecilia Chang ◽  
Prunella Ing ◽  
Kristina Cook ◽  
Kelly McKelvey ◽  
...  
Keyword(s):  
Dna Damage ◽  
Tumor Cells ◽  
Combination Treatment ◽  
High Throughput Screening ◽  
Tumor Hypoxia ◽  
Triple Combination ◽  
Triple Combination Therapy ◽  
Protein Levels ◽  
Approved Drugs

Abstract DIPG is the leading cause of brain tumor-related death in children. Radiotherapy is the only treatment that offers transient benefit and provides palliative care. DIPGs are hypo-perfused with tumor cells being exposed to hypoxia, a potent barrier to effective radiotherapy. Reducing the oxygen consumption rate (OCR) is therefore a potential strategy to reduce tumor hypoxia. We therefore performed a high-throughput screening with 1963 FDA-approved drugs that could reduce tumor hypoxia and OCR, thereby improving radiosensitivity of DIPGs. A subset of anti-diabetic drugs was identified, with phenformin amongst the most potent. It significantly reduced OCR in a panel of DIPG cultures and subsequently suppressed hypoxia in 3-dimensional DIPG neurosphere models that mimic the hypoxic microenvironment. In addition, phenformin demonstrated greater anti-tumor activity and radiosensitizing effect with much lower doses compared with metformin, a less potent biguanide that improved radiosensitivity of DIPG in a patient-derived xenograft (PDX) model in our previous study. The effect of phenformin was further enhanced by combining a second drug dichloroacetate that simultaneously attenuated phenformin-induced acidification rate. Specifically, the combination of phenformin and dichloroacetate induced higher levels of hypoxia inhibition, reactive oxygen species, DNA damage and apoptosis. RNA sequencing demonstrated significant changes induced by the combination treatment in cell-cycle, DNA repair, unfolded protein response and alternative energetic pathways. These changes were further validated by PCR array and western blotting at mRNA and protein levels. In addition, two master regulators that enhance the metabolic capacity of tumor cells through increased glycolysis thus contributing to radioresistance, HIF-1α and c-Myc, were also significantly suppressed by combination treatment. Ultimately, the triple combination of phenformin, DCA and irradiation demonstrated the most potent efficacy in inducing DNA damage, apoptosis and clonogenic inhibition in DIPG cultures. This promising triple combination therapy is currently being tested in our PDX cohort in vivo.

Natural Bioactive Compounds As Adjuvant Therapy For Hepatitis C Infection

2020 ◽  
Vol 16 ◽  
Author(s):  
Moema S. Santana ◽  
Rute Lopes ◽  
Isabela H. Peron ◽  
Carla R. Cruz ◽  
Ana M. M. Gaspar ◽  
...  
Keyword(s):  
Hepatitis C ◽  
Bioactive Compounds ◽  
Low Cost ◽  
Chemical Diversity ◽  
Acute Hepatitis C ◽  
Hepatitis C Infection ◽  
Middle Income ◽  
Broad Perspective ◽  
Cost Of Production

Background: Hepatitis C virus infection is a significant global health burden, which causes acute or chronic hepatitis. The acute hepatitis C is generally asymptomatic and progresses to cure, while persistent infection can progress to chronic liver disease and extrahepatic manifestations. Standard treatment is expensive, poorly tolerated, and has variable sustained virologic responses amongst the different viral genotypes. New therapies involve direct acting antivirals; however, it is also very expensive and may not be accessible for all patients worldwide. In order to provide a complementary approach to the already existing therapies, natural bioactive compounds are investigated as to their several biologic activities, such as direct antiviral properties against hepatitis C, and effects on mitigating chronic progression of the disease, which includes hepatoprotective, antioxidant, anticarcinogenic and anti-inflammatory activities; additionally, these compounds present advantages, as chemical diversity, low cost of production and milder or inexistent side effects. Objective: To present a broad perspective on hepatitis C infection, the chronic disease, and natural compounds with promising anti-HCV activity. Methods: This review consists of a systematic review study about the natural bioactive compounds as a potential therapy for hepatitis C infection. Results: The quest for natural products have yielded compounds with biologic activity, including viral replication inhibition in vitro, demonstrating antiviral activity against hepatitis C. Conclusion: One of the greatest advantages of using natural molecules from plant extracts is the low cost of production, not requiring chemical synthesis, which can lead to less expensive therapies available to low and middle-income countries.

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