Statins: a repurposed drug to fight cancer.
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ABSTRACT:
SUBMITTER: Jiang W
PROVIDER: S-EPMC8306262 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose of reviewRepurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here.Recent findingsIn the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with "target" trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.
| S-EPMC7882549 | biostudies-literature
Project description:The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has overwhelmed healthcare systems requiring the rapid development of treatments, at least, to reduce COVID-19 severity. Drug repurposing offers a fast track. Here, we discuss the potential beneficial effects of statins in COVID-19 patients based on evidence that they may target virus receptors, replication, degradation, and downstream responses in infected cells, addressing both basic research and epidemiological information. Briefly, statins could modulate virus entry, acting on the SARS-CoV-2 receptors, ACE2 and CD147, and/or lipid rafts engagement. Statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects. The well-known anti-inflammatory properties of statins, by blocking several molecular mechanisms, including NF-κB and NLRP3 inflammasomes, could limit the "cytokine storm" in severe COVID-19 patients which is linked to fatal outcome. Finally, statin moderation of coagulation response activation may also contribute to improving COVID-19 outcomes. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.
| S-EPMC7323198 | biostudies-literature
Project description:Lung cancer patients are at heightened risk for developing COVID-19 infection as well as complications due to multiple risk factors such as underlying malignancy, anti-cancer treatment induced immunosuppression, additional comorbidities and history of smoking. Recent literatures have reported a significant proportion of lung cancer patients coinfected with COVID-19. Chloroquine, hydroxychloroquine, lopinavir/ritonavir, ribavirin, oseltamivir, remdesivir, favipiravir, and umifenovir represent the major repurposed drugs used as potential experimental agents for COVID-19 whereas azithromycin, dexamethasone, tocilizumab, sarilumab, famotidine and ceftriaxone are some of the supporting agents that are under investigation for COVID-19 management. The rationale of this review is to identify potential drug-drug interactions (DDIs) occurring in lung cancer patients receiving lung cancer medications and repurposed COVID-19 drugs using Micromedex and additional literatures. This review has identified several potential DDIs that could occur with the concomitant treatments of COVID-19 repurposed drugs and lung cancer medications. This information may be utilized by the healthcare professionals for screening and identifying potential DDIs with adverse outcomes, based on their severity and documentation levels and consequently design prophylactic and management strategies for their prevention. Identification, reporting and management of DDIs and dissemination of related information should be a major consideration in the delivery of lung cancer care during this ongoing COVID-19 pandemic for better patient outcomes and updating guidelines for safer prescribing practices in this coinfected condition.
| S-EPMC7670900 | biostudies-literature
Project description:The rapid breakout of the coronavirus disease of 2019 (COVID-19) has been declared pandemic with serious global concern due to high morbidity and mortality. As we enter the phase beyond limitations there is an urgent need for explicit treatment against COVID-19. To face this immediate global challenge, drug development from scratch is a lengthy process and unrealistic to conquer this battle. Drug repurposing is an emerging and practical approach where existing drugs, safe for humans, are redeployed to fight this harder to treat disease. A number of multi clinical studies have repurposed combined cocktail (remdesivir + chloroquine and favipiravir + chloroquine) to be effective against COVID-19. However, the exact mechanistic aspect has not yet been revealed. In the present study, we have tried to decipher the mechanistic aspects of existing medicines at the viral entry and replication stage via the structural viroinformatics approach. Here we implied the molecular docking and dynamic simulations with emphasis on the unique structural properties of host receptor angiotensin-converting enzyme 2 (ACE2), SARS-CoV2 spike protein and RNA dependent RNA polymerase enzyme (RdRp) of the SARS-CoV2. Deep structural analysis of target molecules exposed key binding residues and structural twists involved in binding with important pharmacophore features of existing drugs [(7-chloro-N-[5-(diethylamino)pentan-2-yl]quinolin-4-amine (chloroquine),N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide N-[[4-(4-methylpiperazin-1-yl)phenyl]methyl]-1,2-oxazole-5-carboxamide) (SSAA09E2), 2-ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-5-cyano-3 (remdesivir) and 6-Fluor-3-oxo-3,4-dihydro-2-pyrazincarboxamid (favipiravir)]. It is evident from this structural informatics study that combo of chloroquine + SSAA09E2 with remdesivir or favipiravir could significantly restrain the virus at the entry and replication stage. Thus, drug repurposition is an attractive approach with reduced time and cost to treat COVID-19, we don't have enough time as the whole world is lockdown and we are in urgent need of an obvious therapeutics' measures.
| S-EPMC7443089 | biostudies-literature
Project description:Currently, there are no treatment options available for the deadly contagious disease, coronavirus disease 2019 (COVID-19). Drug repurposing is a process of identifying new uses for approved or investigational drugs and it is considered as a very effective strategy for drug discovery as it involves less time and cost to find a therapeutic agent in comparison to the de novo drug discovery process. The present review will focus on the repurposing efficacy of the currently used drugs against COVID-19 and their mechanisms of action, pharmacokinetics, dosing, safety, and their future perspective. Relevant articles with experimental studies conducted in-silico, in-vitro, in-vivo, clinical trials in humans, case reports, and news archives were selected for the review. Number of drugs such as remdesivir, favipiravir, ribavirin, lopinavir, ritonavir, darunavir, arbidol, chloroquine, hydroxychloroquine, tocilizumab and interferons have shown inhibitory effects against the SARS-CoV2 in-vitro as well as in clinical conditions. These drugs either act through virus-related targets such as RNA genome, polypeptide packing and uptake pathways or target host-related pathways involving angiotensin-converting enzyme-2 (ACE2) receptors and inflammatory pathways. Using the basic knowledge of viral pathogenesis and pharmacodynamics of drugs as well as using computational tools, many drugs are currently in pipeline to be repurposed. In the current scenario, repositioning of the drugs could be considered the new avenue for the treatment of COVID-19.
| S-EPMC7474498 | biostudies-literature
Project description:Fungal infections have become a clinical challenge due to the emergence of drug-resistance of invasive fungi and a rapid increase of novel pathogens. The development of drug resistance has further restricted the use of antifungal agents. Therefore, there is anurgentneedto searchforalternativetreatmentoptions for Cryptococcus neoformans (C. neoformans). Disulfiram (DSF) has a high human safety profile and promising applications as an antiviral, antifungal, antiparasitic, and anticancer agent. In contrast, the effect of DSF on Cryptococcus has yet to be thoroughly researched. This study investigated the antifungal effect and mechanism of DSF againstC. neoformansto provide a new theoretical foundation for treating Cryptococcal infections. In vitro studies demonstrated that DSF inhibitedCryptococcusat minimum inhibitory concentrations (MICs) ranging from 1.0 to 8.0 μg/mL. Combined antifungal effects were also observed with 5-fluorocytosine, amphotericin B, terbinafine, or ketoconazole. In vivo, DSF exerted asignificantprotectiveeffectforGalleria mellonella infected with C. neoformans.Mechanistic investigations showed that DSF dose-dependently inhibited the melanin, urease, acetaldehyde dehydrogenase, capsule, and biofilm formation or viability ofC. neoformans.Further study indicated DSF affectedC. neoformansby interfering with multiple biological pathways, including replication, metabolism, membrane transport, and biological enzyme activity. Potentially essential targets of these pathways included acetaldehyde dehydrogenase, catalase, ATP-binding cassette transporter (ABC transporter) AFR2, and iron-sulfur cluster transporter ATM1. These findings contribute to the understanding of mechanisms inC. neoformans, and provide new insights for the application of DSF.
2023-12-31 | GSE248987 | GEO
Project description:Drug repurposing is a complementary pathway for introducing new drugs against cancer. Broad systematic assessments of ongoing repurposing efforts in oncology are lacking, but may be helpful to critically appraise current and future efforts. Hence, we conducted a systematic PubMed search encompassing 100 frequently prescribed and 100 randomly selected drugs, and assessed the published preclinical anti-cancer effects. Furthermore, we evaluated all the identified original articles for methodological quality. We found reports indicating anti-cancer effects for 138/200 drugs, especially among frequently prescribed drugs (81/100). Most were reports suggesting single-agent activity of the drugs (61%). Basic information, such as the cell line used or control treatments utilized, were reported consistently, while more detailed information (e.g., excluded data) was mostly missing. The majority (56%) of in vivo studies reported randomizing animals, while only few articles stated that the experiments were conducted in a blinded fashion. In conclusion, we found promising reports of anti-cancer effects for the majority of the assessed drugs, but speculate that many of them are false-positive findings. Reward systems should be adjusted to encourage the widespread usage of high reporting quality and bias-reducing methodologies, aiming to decrease the rate of false-positive results, and thereby increasing the trust in the findings.
| S-EPMC8699650 | biostudies-literature
Project description:Repurposing of approved non-antitumor drugs represents a promising and affordable strategy that may help to increase the repertoire of effective anticancer drugs. Benzimidazole-based anthelmintics are antiparasitic drugs commonly employed both in human and veterinary medicine. Benzimidazole compounds are being considered for drug repurposing due to antitumor activities displayed by some members of the family. In this study, we explored the effects of a large series of benzimidazole-based anthelmintics (and some enantiomerically pure forms of those containing a stereogenic center) on the viability of different tumor cell lines derived from paraganglioma, pancreatic and colorectal cancer. Flubendazole, parbendazole, oxibendazole, mebendazole, albendazole and fenbendazole showed the most consistent antiproliferative effects, displaying IC50 values in the low micromolar range, or even in the nanomolar range. In silico evaluation of their physicochemical, pharmacokinetics and medicinal chemistry properties also provided useful information related to the chemical structures and potential of these compounds. Furthermore, in view of the potential repurposing of these drugs in cancer therapy and considering that pharmaceutically active compounds may have different mechanisms of action, we performed an in silico target prediction to assess the polypharmacology of these benzimidazoles, which highlighted previously unknown cancer-relevant molecular targets.
| S-EPMC8072969 | biostudies-literature
Project description:The current outbreak of SARS-CoV-2 virus has caused a large increase in mortality and morbidity associated with respiratory diseases. Huge efforts are currently ongoing to develop a vaccine against this virus. However, alternative approaches could be considered in the fight against this disease. Among other strategies, structural-based drug design could be an effective approach to generate specific molecules against SARS-CoV-2, thus reducing viral burden in infected patients. Here, in addition to this structural approach, we also revise several therapeutic strategies to fight against this viral threat. Furthermore, we report ACE-2 genetic polymorphic variants affecting residues involved in close contacts with SARS-CoV-2 that might be associated to different infection risks. These analyses could provide valuable information to predict the course of the disease.
| S-EPMC7477106 | biostudies-literature
Project description:BackgroundTreatments are needed to address the growing prevalence of Alzheimer's disease (AD). Clinical trials have failed to produce any AD drugs for Food and Drug Administration (FDA) approval since 2003, and the pharmaceutical development process is both time-consuming and costly. Drug repurposing provides an opportunity to accelerate this process by investigating the AD-related effects of agents approved for other indications. These drugs have known safety profiles, pharmacokinetic characterization, formulations, doses, and manufacturing processes.MethodsWe assessed repurposed AD therapies represented in Phase I, Phase II, and Phase III of the current AD pipeline as registered on ClinicalTrials.gov as of February 27, 2020.ResultsWe identified 53 clinical trials involving 58 FDA-approved agents. Seventy-eight percent of the agents in trials had putative disease-modifying mechanisms of action. Of the repurposed drugs in the pipeline 20% are hematologic-oncologic agents, 18% are drugs derived from cardiovascular indications, 14% are agents with psychiatric uses, 12% are drug used to treat diabetes, 10% are neurologic agents, and the remaining 26% of drugs fall under other conditions. Intellectual property strategies utilized in these programs included using the same drug but altering doses, routes of administration, or formulations. Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry. We compared our results to a European trial registry and found results similar to those derived from ClinicalTrials.gov.ConclusionsDrug repurposing is a common approach to AD drug development and represents 39% of trials in the current AD pipeline. Therapies from many disease areas provide agents potentially useful in AD. Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.
| S-EPMC7433208 | biostudies-literature