Statins as anti‐tumor agents: A paradigm for repurposed drugs

Cancer Reports, Journal Year: 2024, Volume and Issue: 7(5)

Published: May 1, 2024

Abstract Background Statins, frequently prescribed medications, work by inhibiting the rate‐limiting enzyme HMG‐CoA reductase (HMGCR) in mevalonate pathway to reduce cholesterol levels. Due their multifaceted benefits, statins are being adapted for use as cost‐efficient, safe and effective anti‐cancer treatments. Several studies have shown that specific types of cancer responsive statin medications since they rely on growth survival. Recent Findings Statin a class drugs known potent inhibition production typically treat high Nevertheless, there is growing interest repurposing treatment malignant neoplastic diseases, often conjunction with chemotherapy radiotherapy. The mechanism behind includes targeting apoptosis through BCL2 signaling pathway, regulating cell cycle via p53‐YAP axis, imparting epigenetic modulations altering methylation patterns CpG islands histone acetylation downregulating DNMTs HDACs respectively. Notably, some suggested potential chemo‐preventive effect, decreased occurrence tumor relapse enhanced survival rate were reported patients undergoing long‐term therapy. However, definitive endorsement usage therapy hinges population based clinical larger patient cohorts extended follow‐up periods. Conclusions properties seems reach beyond influence production. Further investigations necessary uncover effects promoting pathways. Given distinct attributes, might emerge promising contenders fight against tumorigenesis, appear enhance efficacy address limitations conventional

Language: Английский

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Targeting cholesterol-dependent adrenal steroidogenesis for management of primary aldosteronism

Trends in Endocrinology and Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Computational Drug Repositioning in Cardiorenal Disease: Opportunities, Challenges, and Approaches

PROTEOMICS, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 31, 2025

There is currently increased interest in drug repositioning programs, namely the identification of new therapeutic areas for already approved drugs, both academia as well biotech and pharmaceutical industry. Since 2012, number publications indexed MEDLINE on or repurposing exponentially increasing with a peak year 2021 due to worldwide search options combat COVID-19 pandemic [1]. Drug repositioning, however, not new, companies have ever since been looking additional market opportunities their products, particular when patents expire generics manufacturers enter initial approvals [2, 3]. In pharma world, term indication expansion also often used instead repurposing. patients suffering from rare disease who are lacking any therapies, represents very interesting efficient way bringing treatment patient fast [4]. This has stressed recent position paper International Rare Disease Research Consortium [5]. Several international consortia recognized trend toward Two US-based endeavors focusing Repurposing Hub EveryCure. Researchers Broad Institute created aim construct curate library FDA drugs that can be systematic screenings [6]. EveryCure's mission identify novel diseases via computational repositioning. European initiatives context Repo4EU (https://repo4.eu/) REMEDi4ALL (https://remedi4all.org/) consortia, being public–private partnerships develop tools but apply these selected indications. Next effort COVID-19, there at least three reasons why programs gaining momentum. First, molecular characterization processes continuously improving, we understand more about key pathways disease-modifying proteins, forming basis find counterbalancing dysregulations level. Second, arsenal tools, methods, workflows getting better matching pathobiology mechanism action (MoA), identifying connections thus potential targets intervention. And third, list successful cases longer. Even current blockbuster GLP1 agonists seen positive examples, scientifically commercially. Initially developed diabetes mellitus, this compound class meantime obesity clinical development several indications across different areas. viewpoint article, will discuss (i) experimental approaches discover opportunities, (ii) challenges further discovered compounds, (iii) kidney cardiovascular (CVD). observation-driven trials practice methods such binding assays phenotype screens, systematically opportunities. These make use information direct targets, affected biological mechanisms, side effects, omics signatures action, data electronic health records (EHRs) registries [7-10]. Key given Figure 1 discussed following sections. A major challenge one most crucial early steps discovery selection an appropriate target. For majority target known, always responsible drug's full efficacy potential. Information nevertheless target-based by which causally linked and/or progression [11]. Databases holding drug-target relations include, example, DrugBank [12], Therapeutic Target Database [13], STITCH EMBL-EBI [14]. open-source aiming consolidate sources associate Open Targets platform [15] Pharos [16]. comprehensive integrates types genetic associations, gene expression data, pathway information, results literature-mining prioritize human diseases. The driven researchers collaboration between scientific institutions companies. Users option either evaluating individual proteins (potential targets) searching (phenotype) [15]. web application consolidating established "Illuminating Druggable Genome" consortium Like Targets, users (protein) presented lists ranked respectively. Protein furthermore classified into four categories, Tclin (targets, drug), Tchem activity cutoff <30 nM), Tbio high annotation score based literature antibodies targeting protein), Tdark (targets without known compounds low scores literature). Especially category prime candidates approaches. Si et al. recently identified set promising chronic analysis proteomics transcriptomics combination Mendelian randomization investigation protein–protein interactions colocalization protein-coding genes [17]. might pave beneficially impact course disease. Fu similar approach evaluate relevance medications osteoarthritis [18]. They propose thiazolidinediones agents predicted role PPARG progression. protein structure-based Structure-based cheminformatics than bioinformatics-driven leverage structural similarities same drugs. Known pharmacokinetic profiles safety approach. broadly traditional advanced AI/ML-aided high-quality structures receptor ligands. Traditional high-throughput vitro, whereas machine learning algorithms process facilitates docking simulations, accuracy efficiency [19]. core strategy contrast only focus single compare whole (i.e., patterns abundance changes) various those reverse signature [20]. landmark study was published 2006 Lamb making 164 transcriptome level, dataset they called Connectivity Map [21]. meantime, extended thousands signature-based "connectivity mapping". To generate total over million profiles, focused 1000 encode 80% variation transcriptional creating L1000 [22]. integrated other resources within Library Integrated Network-based Cellular Signatures (LINCS) program, including proteomic, metabolomic, epigenomic [23]. publicly available accessible iLINCS web-based [24]. applications Mergeomics 2.0 R package integrating multi-omics reveal insights pathways, networks, drivers important pathogenesis ultimately predict [25]. functional module PharmOmics matches multi-omics-informed networks [26]. designed enable summary statistics multiomics sets, networks. PharmGWAS database leverages genome-wide association studies (GWAS) candidate repurposing, resistance, (iv) effects broad range GWAS datasets retrieved biobanks consortiums, deposited compound-perturbed CMap2.0 SigCom LINCS [27]. Single-cell Guided Pipeline Aid Drugs (ASGARD) uses scRNA-Seq samples attempts highest respective [28]. aims model complex systems level analyze among entities, diseases, By mapping onto network, measurements connectivity, proximity, cluster formation interactions, regulatory allow predictions silico Guala Sonnhammer tested network crosstalk-based constructed benchmark performance assessment network-based [29]. cross-talk sets disease-related genes, calculated distinct measures. evaluated shortest path every its closest [30], separate estimate crosstalk links two nodes [31-33]. Sadegh proposed (NeDRex) gene, protein, drug, target, annotations relationships [34]. NeDRex incorporates state-of-the-art case exemplified applicability extracting meaningful ovarian cancer starting seed nodes. obtained contained newly connector which, together participate relevant could using alone. Maier Drugst.one provides user-friendly, utilities interactive visualization capabilities [35]. 14 covering protein/gene, tool enrich proteins/genes clinically associations. Other include integration display adjacent project network. Yang DRONet framework effectiveness comparative combining embeddings, generated heterogeneous drug-disease ranking specific utilizing like RankNet, LambdaRank, LambdaMART [36]. Advances DNA/RNA sequencing enabled models derived mapped interactome Cheng Genome-wide Positioning Systems whole-exome approximately 5000 15 taken Cancer Genome Atlas, prioritizing [37]. Validation showed ouabain, cardiac arrhythmia heart failure, exhibited significant antitumor lung adenocarcinoma pathways. Moreover, another group proximity hundreds drug–disease associations [38]. validated against large-scale supported mechanistic vitro demonstrating risk coronary artery carbamazepine decreased hydroxychloroquine, compared levetiracetam. highlights interactome-based uncovering existing understanding broader Fiscon stated footprints randomly scattered colocalized highly interconnected subnetworks [39]. effective off-target adverse should proximal module. frameworks five metrics, breast prostate neoplasms, schizophrenia, liver cirrhosis. Ruiz introduced multiscale interactome, method disease-perturbed functions [40]. Their comprised 17,660 9798 functions, 1661 840 performing random walks evaluates propagation indirect enabling prediction treatments, related alter treatments reactions. comparing diffusion research groups atopic dermatitis [41], [42], non-alcoholic fatty [43], metabolic syndrome [44], cardiorenal later section examples rather just leveraging drug-specific dysregulations. REpurposing BIOlogical Pathways (DREBIOP) exemplary concepts comprehensively utilizes where effect mediated through [45]. authors exemplify beneficial ergocalciferol rickets interference vitamin D pathway. Another example pathway-based subtypes driver overcome resistance [46]. Knowledge-based enhance incorporating domain-specific knowledge graph-based structures, tasks providing deeper interactions. Graph embeddings advance multi-modal nodes, relationships, entire sub-graphs low-dimensional vectors. Himmelstein modeled graph 11 entities 24 relationship types, 29 public cover anatomies, pharmacologic classes, symptoms, entity [47]. paths correlating compound–disease pairs previously shown effective. Additionally, were DrugCentral trial data. eight epilepsy. Jain address issue insufficient specificity work [48]. Diluted coarse clustering limit ability synergies. Therefore, create hypergraphs, hyperedges this, converted modification node2vec algorithm. KG. Seven Alzheimer's Ghorbanali homogeneous features along negative unified latent space [49]. unknown sub-graph. Prediction area under curve ∼90% achieved. coronavirus infection skin-related predicted, conditions having demonstrated studies. Santos provide infrastructure facilitate automatic analysis, visualization, extraction [50]. 26 biomedical databases, literature. It built precision medicine decision-making. Machine graph. Its significantly higher CT45 serous adenocarcinoma, confirming biomarker long-term survival. Amiri Souri DT2Vec+ link [51]. shows predicting degree type proposing cancer-specific biomarkers. Lobentanzer unify fragmented landscape simplify task-specific KGs [52]. Biocypher offers focuses modularity, reproducibility, harmonization, reusability, accessibility. builds top rigid standards allows exchanges, modifications, extensions ontologies map concepts. Multiple act proof concept demonstrate practical use, federated Care-for-Rare project, multiple children's hospitals collaborate train shared while keeping decentralized private locally employed, sharing model's configuration parameters anonymous results. active hold combined ML unravel reported As articles almost tripled last decade continues grow 850,000 abstracts annually, increasingly relies automated text mining natural language processing methods. Deep technologies long short-term memory, convolutional neural bidirectional encoder representations transformers [53]. Challenges abbreviations ambiguity terms, symbols identical common phrases unspecific sub-strings falsely part longer, entries. contrast, rule-based definition stringent domain experts. Although involves manual curation longer cycles, it overall certain [54]. extract ideally causal genes/proteins, form intermediate genes/proteins. commonly resource storing genes/proteins DisGeNet [55]. Similarities Kumar epilepsy paroxetine seizures [56]. Data extracted SIDER [57], however seems no maintained update dates back 2015. events event reporting system still regularly updated. Paci measure reposition CVDs [58, 59]. formulated side-effect distal effects. vast amounts real-world captured EHRs, demographics, diagnoses, outcomes, lab results, explore correlations outcomes originally [60]. Retrospective analyses EHR hand lead de-novo validate findings Metformin, primarily therapy diabetes, found reduce dementia 2 after statistical databases [61]. Deep-learning emulate retrospective large Liu [62]. UK Biobank valuable around half participants deidentified [https://www.ukbiobank.ac.uk/]. 10 years. attractive addressing questions beyond exploration events, comorbidities groups. Main screenings. screen wide manner. High-throughput target-binding screening rely cellular animal prior targets. interact potentially modulate [63]. Phenotype usually performed cell-based determining readouts cell viability, apoptosis, motility, morphology, monitor signaling Asawa al., 8000 viability polycystic cells anti-proliferative [64]. Observations considered serendipitous play field led past [65]. prominent sildenafil initially systemic hypertension erectile dysfunction observed "side effects" [66], minoxidil treat inducing hair regrowth alopecia areata [67], amantadine influenza now symptoms Parkinson's [68]. Most until findings. Accessible Biobank, datasets, paved data-driven too determine biology-driven probability success viable eventually mix complementary applied increase chances success. holds references conducted renal No matter discovered, first step clinic next chapter. Repositioning described shortcut time drastically decrease costs. Widely figures report takes 10000 start end up average 10–17 years comes mean price tag 1.6 2.8 billion USD [69, 70]. exact savings achieved time, risk, money unclear, some conflicting evidence. Some reviews suggest 30% efforts product marketing, 10% (NDAs) general, argue repurposed do necessarily rates limiting factor [71]. Once utilization marketing remains cost-intensive challenge, referred "valley death" basic [72]. Numerous experts state benefit lies availability profile preclinical test even (safety) may skipped Phase II III. criteria, straightforward obvious, as: safe studies, does adequately rec

Language: Английский

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A randomized phase II/III trial of rosuvastatin with neoadjuvant chemo-radiation in patients with locally advanced rectal cancer

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 19, 2025

Aim Statins have been shown to improve the possibility of a pathological complete response (pCR) in patients with locally advanced rectal cancer when given combination neo-adjuvant chemo-radiation (NACTRT) observational studies. The primary objective this phase II randomized controlled trial (RCT) is determine impact rosuvastatin improving pCR rates who are undergoing NACTRT. secondary objectives compare adverse events, postoperative morbidity and mortality, disease-free survival (DFS), overall two arms identify potential prognostic predictive factors determining outcomes. If study positive, we plan proceed III RCT 3-year DFS as endpoint. Methods This prospective, randomized, open-label II/III study. has sample size 316 (158 each arm) be accrued over 3 years 288 evaluable patients. standard arm will receive NACTRT while intervention group 20 mg orally once daily along for 6 weeks followed by alone 6–10 until surgery. All reviewed after repeat imaging multidisciplinary tumor board at 12–16 starting operable planned rate, regression grade (TRG), post-surgical complications recorded. Conclusion addition may oncological outcomes increasing likelihood would low-cost, low-risk that could potentially lead refinement strategies, such “watch wait”, select subgroup Clinical registration Trials Registry India, identifier CTRI/2018/11/016459.

Language: Английский

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Lipid metabolism dysregulation for bone metastasis and its prevention

Expert Review of Anticancer Therapy, Journal Year: 2025, Volume and Issue: unknown

Published: April 12, 2025

Bone metastasis often develops in advanced malignancies. Lipid metabolic dysregulation might play pivotal role cancer progression and subsequent deterioration of bone health at metastatic condition. In-depth understanding lipid reprogramming metastasized cells other stromal including marrow adipocyte (BMA) is an urgent need to develop effective therapy. This paper emphasizes providing overview multifaceted dysregulated lipids BMA association with by utilizing search terms metabolism, PubMed. study extends address mechanism linked metabolism various crucial genes (e.g. CSF-1, RANKL, NFkB NFATc1) involved metastasis. review examines therapeutic strategies targeting offer potential avenues disrupt lipid-driven On condition, molecules especially not only favors but also potentiate within cells. Distinct lipid-metabolism associated may act as biomarker, these challenging task for specific treatment. Curbing function resorption controlling drugs statins, omega-3 FA metformin) provide additional support curtail lipid-associated

Language: Английский

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Lck Function and Modulation: Immune Cytotoxic Response and Tumor Treatment More Than a Simple Event

Cancers, Journal Year: 2024, Volume and Issue: 16(15), P. 2630 - 2630

Published: July 24, 2024

Lck, a member of the Src kinase family, is non-receptor tyrosine involved in immune cell activation, antigen recognition, tumor growth, and cytotoxic response. The enzyme has usually been linked to T lymphocyte activation upon recognition. Lck central CD4, CD8, NK activation. However, recently, it become clearer that activating CD8 cells can be independent presentation enhance role function controversial similar fashion as CAR cells. Inhibiting kinases highly successful approach treating hematologic malignancies. inhibitors may useful other types, they prevent exhaustion. New, more selective have documented, shown interesting activities not only growth but treatment autoimmune diseases, asthma, graft vs. host disease. Drug repurposing bioinformatics aid solving several unsolved issues about cancer. In summary, response simple event requires research.

Language: Английский

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Molecular Mechanisms Underlying the Anticancer Properties of Pitavastatin against Cervical Cancer Cells

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7915 - 7915

Published: July 19, 2024

Cervical cancer ranks as the fourth most prevalent form of and is a significant contributor to female mortality on global scale. Pitavastatin an anti-hyperlipidemic medication has been demonstrated exert anticancer anti-inflammatory effects. Thus, purpose this study was evaluate effect pitavastatin cervical underlying molecular mechanisms involved. The results showed that significantly inhibited cell viability by targeting cell-cycle arrest apoptosis in Ca Ski, HeLa C-33 A cells. caused sub-G1- G0/G1-phase Ski cells G2/M-phase Moreover, induced via activation poly-ADP-ribose polymerase (PARP), Bax cleaved caspase 3; inactivated expression Bcl-2; increased mitochondrial membrane depolarization. Furthermore, slowed migration all three lines, mediated PI3K/AKT MAPK (JNK, p38 ERK1/2) pathways. markedly tumor growth vivo cell-originated xenograft mouse model. Overall, our identified agent for cancer, which might be expanded clinical use future.

Language: Английский

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Microneedles integrated with atorvastatin-loaded pumpkisomes for breast cancer therapy: A localized delivery approach

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 376, P. 354 - 368

Published: Oct. 19, 2024

Language: Английский

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Statins attenuate Wnt/β-catenin signaling by targeting SATB family proteins in colorectal cancer

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 26, 2024

Abstract Colorectal cancer is the second leading cause of cancer-related deaths worldwide, highlighting need for improved treatments and advanced molecular research. A recent therapeutic approach focuses on repurposing drugs to target dysregulated pathways involved in tumorigenesis. Among these, statins, commonly known lowering cholesterol, have attracted attention their potential anti-cancer properties. Here, we provide direct evidence same by assessing impact statin treatment lipid, transcript, protein levels. Our findings reveal that statins specifically key components Wnt/β-catenin pathway, a major factor adenoma formation, including SATB (Special AT-rich Binding protein) family proteins. While SATB1 recognized as regulator tumorigenesis, particularly under Wnt signaling, SATB2 appears exert an opposing role. We demonstrate reciprocally alters expression pattern these Furthermore, human clinical trial evaluating therapy supports hypothesis differential proteins crucial tumorigenic outcomes. In conclusion, this modulation suggests promising new avenues through drug repurposing.

Language: Английский

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Statins decrease the risk of hepatocellular carcinoma in metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis

World Journal of Experimental Medicine, Journal Year: 2024, Volume and Issue: 14(4)

Published: Oct. 29, 2024

BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic with significant risk developing hepatocellular carcinoma (HCC). Recent clinical evidence indicates the potential benefits statins in cancer chemoprevention and therapeutics. However, it still unclear if can lower specific HCC among patients MASLD. AIM To investigate impact statin use on development METHODS A systematic review meta-analysis all studies was performed that measured effect occurrence The difference between users non-users calculated MASLD patients. We also evaluated lipophilic versus hydrophilic cumulative dose reduction. RESULTS total four consisting 291684 were included. therapy had 60% pooled compared to non-statin group [relative (RR) = 0.40, 95%CI: 0.31-0.53, I2 16.5%]. Patients taking reduced (RR 0.42, 0.28-0.64), whereas those not shown reduction 0.57, 0.27-1.20). higher (> 600) defined daily doses (cDDD) 70% 0.30, 0.21-0.43). There 29% 0.71, 0.55-0.91) 43% 0.40-0.82) decreased receiving 300-599 cDDD 30-299 cDDD, respectively. CONCLUSION Statin lowers lipophilicity correlate

Language: Английский

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