Curr Oncol. 2024 Oct 8;31(10):6032-6049. doi: 10.3390/curroncol31100450.

ABSTRACT

Ritonavir is a protease inhibitor initially developed for HIV treatment that is now used as a pharmacokinetic booster for other antiretrovirals due to it being a cytochrome P450 3A4 enzyme and P-glycoprotein inhibitor. Consequently, ritonavir is of special interest for repurposing in other diseases. It had an important role in battling the COVID-19 pandemic as a part of the developed drug Paxlovid® in association with nirmatrelvir and has shown effects in hepatitis and other pathogenic diseases. Ritonavir has also shown promising results in overcoming drug resistance and enhancing the efficacy of existing chemotherapeutic agents in oncology. Evidence of cancer repurposing potential was demonstrated in cancers such as ovarian, prostate, lung, myeloma, breast, and bladder cancer, with several mechanisms of action presented. In vitro studies indicate that ritonavir alone can inhibit key pathways involved in cancer cell survival and proliferation, causing apoptosis, cell cycle arrest, endoplasmic reticulum stress, and metabolic stress due to the inhibition of molecules like heat shock protein 90 and cyclin-dependent kinases. Ritonavir also causes resistant cells to become sensitized to anticancer drugs like gemcitabine or docetaxel. These findings indicate that repurposing ritonavir, either on its own or in combination with other medications, could be a promising approach for treating various diseases. This is particularly relevant in cancer therapy, where ritonavir repurposing is the central focus of this review.

PMID:39451754 | DOI:10.3390/curroncol31100450

Nat Med. 2024 Oct 24. doi: 10.1038/s41591-024-03333-8. Online ahead of print.

NO ABSTRACT

PMID:39448863 | DOI:10.1038/s41591-024-03333-8

Chemistry. 2024 Oct 24:e202401838. doi: 10.1002/chem.202401838. Online ahead of print.

ABSTRACT

In this work we introduce Target Fisher, a consensus structure-based target prediction tool that integrates molecular docking and machine learning with the aim to aid in the identification of potential biological targets and the optimization of the use of bioassays. Target Fisher uses per-residue energy decomposition profiles extracted from docking poses as fingerprints to train target-specific machine learning models. It provides predictions for a curated set of 37 protein targets, covering a diverse range of biological entities, and offers a user-friendly interface accessible via a web server (https://gqc.quimica.unlp.edu.ar/targetfisher/). In this sense, Target Fisher is a valuable tool to aid organic and medicinal chemistry groups in target identification, drug discovery and drug repurposing. As a case study, we demonstrate the efficacy of Target Fisher by screening a small library of assorted natural products for targets relevant to neurodegenerative diseases, which resulted in the identification and experimental validation of selective inhibitors of monoamine oxidase B (MAO-B).

PMID:39447068 | DOI:10.1002/chem.202401838

Front Pharmacol. 2024 Oct 9;15:1422080. doi: 10.3389/fphar.2024.1422080. eCollection 2024.

ABSTRACT

Depression and Parkinson's disease (PD) are devastating psychiatric and neurological disorders that require the development of novel therapeutic interventions. Drug repurposing targeting predefined pharmacological targets is a widely use approach in modern drug discovery. Monoamine oxidase B (MAO-B) is a critical protein implicated in Depression and PD. In this study, we undertook a systematic exploration of repurposed drugs as potential inhibitors of MAO-B. Exploring a library of 3,648 commercially available drug molecules, we conducted virtual screening using a molecular docking approach to target the MAO-B binding pocket. Two promising drug molecules, Brexpiprazole and Trifluperidol, were identified based on their exceptional binding potential and drug profiling. Subsequently, all-atom molecular dynamics (MD) simulations were performed on the MAO-B-ligand complexes for a trajectory of 300 nanoseconds (ns). Simulation results demonstrated that the binding of Brexpiprazole and Trifluperidol induced only minor structural alterations in MAO-B and showed significant stabilization throughout the simulation trajectory. Overall, the finding suggests that Brexpiprazole and Trifluperidol exhibit strong potential as repurposed inhibitors of MAO-B that might be explored further in experimental investigations for the development of targeted therapies for depression and PD.

PMID:39444620 | PMC:PMC11496130 | DOI:10.3389/fphar.2024.1422080

Front Pharmacol. 2024 Oct 9;15:1419772. doi: 10.3389/fphar.2024.1419772. eCollection 2024.

ABSTRACT

Repurposing generic drugs as new treatments for life-threatening diseases such as cancer is an exciting yet largely overlooked opportunity due to a lack of market-driven incentives. Nonprofit organizations and other non-manufacturers have been ramping up efforts to repurpose widely available generic drugs and rapidly expand affordable treatment options for patients. However, these non-manufacturers find it difficult to obtain regulatory approval in the U.S. Without a straightforward path for approval and updating drug labeling, non-manufacturers have relied on off-label use of repurposed drugs. This limits the broad clinical adoption of these drugs and patient access. In this paper, we explore the regulatory landscape for repurposing of small molecule generic drugs within the U.S. We describe case studies of repurposed drugs that have been successfully incorporated into clinical treatment guidelines for cancer without regulatory approval. To encourage greater adoption of generic drugs in clinical practice-that is, to encourage the repurposing of these drugs-we examine existing Food and Drug Administration (FDA) pathways for approval of new uses or indications for generic drugs. We show how non-manufacturers, who are generally more active in generic drug repurposing than manufacturers, could utilize existing regulatory authorities and pathways, and we describe the challenges they face. We propose an extension of the existing 505(b)(2) new drug application (NDA) approval pathway, called a "labeling-only" 505(b)(2) NDA, that would enable non-manufacturers to seek approval of new indications for well-established small molecule drugs when multiple generic products are already available. It would not require new chemistry, manufacturing, and controls (CMC) data or introducing new drug products into the marketplace. This pathway would unlock innovation broadly and enable patients to benefit from the enormous potential of low-cost generic drugs.

PMID:39444616 | PMC:PMC11496753 | DOI:10.3389/fphar.2024.1419772

Sci Rep. 2024 Oct 23;14(1):25054. doi: 10.1038/s41598-024-76367-0.

ABSTRACT

Accurate prediction of drug-target interactions (DTIs) is crucial for advancing drug discovery and repurposing. Computational methods have significantly improved the efficiency of experimental predictions for drug-target interactions in Western medicine. However, accurately predicting the complex relationships between Chinese medicine ingredients and targets remains a formidable challenge due to the vast number and high heterogeneity of these ingredients. In this study, we introduce the CWI-DTI method, which achieves high-accuracy prediction of DTIs using a large dataset of interactive relationships of drug ingredients or candidate targets. Moreover, we present a novel dataset to evaluate the prediction accuracy of both Chinese and Western medicine. Through meticulous collection and preprocessing of data on ingredients and targets, we employ an innovative autoencoder framework to fuse multiple drug (target) topological similarity matrices. Additionally, we employ denoising blocks, sparse blocks, and stacked blocks to extract crucial features from the similarity matrix, reducing noise and enhancing accuracy across diverse datasets. Our results indicate that the CWI-DTI model shows improved performance compared to several existing state-of-the-art methods on the datasets tested in both Western and Chinese medicine databases. The findings of this study hold immense promise for advancing DTI prediction in Chinese and Western medicine, thus fostering more efficient drug discovery and repurposing endeavors. Our model is available at https://github.com/WANG-BIN-LAB/CWIDTI .

PMID:39443630 | DOI:10.1038/s41598-024-76367-0

Bioinformatics. 2024 Oct 23:btae630. doi: 10.1093/bioinformatics/btae630. Online ahead of print.

ABSTRACT

MOTIVATION: The concept of controllability within complex networks is pivotal in determining the minimal set of driver vertices required for the exertion of external signals, thereby enabling control over the entire network's vertices. Target controllability further refines this concept by focusing on a subset of vertices within the network as the specific targets for control, both of which are known to be NP-hard problems. Crucially, the effectiveness of the driver set in achieving control of the network is contingent upon satisfying a specific rank condition, as introduced by Kalman. On the other hand, structural controllability provides a complementary approach to understanding network control, emphasizing the identification of driver vertices based on the network's structural properties. However, in structural controllability approaches, the Kalman condition may not always be satisfied.

RESULTS: In this study, we address the challenge of target controllability by proposing a feed-forward greedy algorithm designed to efficiently handle large networks while meeting the Kalman controllability rank condition. We further enhance our method's efficacy by integrating it with Barabasi et al.'s structural controllability approach. This integration allows for a more comprehensive control strategy, leveraging both the dynamical requirements specified by Kalman's rank condition and the structural properties of the network. Empirical evaluation across various network topologies demonstrates the superior performance of our algorithms compared to existing methods, consistently requiring fewer driver vertices for effective control. Additionally, our method's application to protein-protein interaction networks associated with breast cancer reveals potential drug repurposing candidates, underscoring its biomedical relevance. This study highlights the importance of addressing both structural and dynamical aspects of network controllability for advancing control strategies in complex systems.

AVAILABILITY: The source code is available for free at: Https://github.com/fatemeKhezry/targetControllability.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:39441804 | DOI:10.1093/bioinformatics/btae630

Cancer Med. 2024 Oct;13(20):e70288. doi: 10.1002/cam4.70288.

ABSTRACT

BACKGROUND AND AIMS: Anti-angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti-angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti-angiogenic inhibitors and identify novel anti-angiogenic drugs with clinical applications.

RESULTS: The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. In vivo, inhibition of the VEGF pathway had no anti-tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti-angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood-brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs in vitro and 005 mouse models in vivo to evaluate genetic changes by RNA-Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non-VEGF-mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model.

CONCLUSION: Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways led to anti-angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti-angiogenic therapy for glioblastoma with safe, low cost, and fast availability.

PMID:39440923 | DOI:10.1002/cam4.70288

Front Oncol. 2024 Oct 8;14:1441460. doi: 10.3389/fonc.2024.1441460. eCollection 2024.

ABSTRACT

Glioblastoma remains the most prevalent and aggressive primary malignant brain tumor in adults, characterized by limited treatment options and a poor prognosis. Previous drug repurposing efforts have yielded only marginal survival benefits, particularly those involving inhibitors targeting receptor tyrosine kinase and cyclin-dependent kinase-retinoblastoma pathways. This limited efficacy is likely due to several critical challenges, including the tumor's molecular heterogeneity, the dynamic evolution of its genetic profile, and the restrictive nature of the blood-brain barrier that impedes effective drug delivery. Emerging diagnostic tools, such as circulating tumor DNA and extracellular vesicles, offer promising non-invasive methods for real-time tumor monitoring, potentially enabling the application of targeted therapies to more selected patient populations. Moreover, innovative drug delivery strategies, including focused ultrasound, implantable drug-delivery systems, and engineered nanoparticles, hold potential for enhancing the bioavailability and therapeutic efficacy of treatments.

PMID:39439947 | PMC:PMC11493774 | DOI:10.3389/fonc.2024.1441460

Cell Genom. 2024 Oct 19:100679. doi: 10.1016/j.xgen.2024.100679. Online ahead of print.

ABSTRACT

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT.

PMID:39437787 | DOI:10.1016/j.xgen.2024.100679

Comput Biol Med. 2024 Oct 21;183:109158. doi: 10.1016/j.compbiomed.2024.109158. Online ahead of print.

ABSTRACT

OBJECTIVE: Computational drug re-purposing has received a lot of attention in the past decade. However, methods developed to date focused on established compounds for which information on both, successfully treated patients and chemical and genomic impact, were known. Such information does not always exist for first-in-class drugs under development.

METHODS: To identify indications (diseases) for drugs under development we extended and tested several unsupervised computational methods that utilize Electronic Health Record (EHR) data.

RESULTS: We tested the methods on known drugs with multiple indications and show that a variant of matrix factorization leads to the best performance for first-in-line drugs improving upon prior methods that were developed for established drugs. The method also identifies novel predictions for key immunology and oncology drugs. Our results show that the performance of re-purposing methods differ greatly between oncology and inflammation/immunology. We hypothesize that the lower performance in oncology can be explained by the fact that many chemotherapies are not targeted therapies.

CONCLUSION: Finding new indications for drugs is extremely valuable. Our results explore how to best use EHR data for finding new indications for first in class drugs drug using a phenotypical-similarity driven approach. Our methods can be integrated with others methods using multiple data modalities such as chemical, molecular, genetic data.

PMID:39437603 | DOI:10.1016/j.compbiomed.2024.109158

Int Immunopharmacol. 2024 Oct 21;143(Pt 2):113403. doi: 10.1016/j.intimp.2024.113403. Online ahead of print.

ABSTRACT

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia. The current study aimed to investigate the potential of empagliflozin (EMPA) to protect against acetylcholine (ACh)/calcium chloride (CaCl2)-induced AF in rats and elucidate the possible underlying mechanism of action. Rats were randomly assigned to five groups, as follows: CTRL group: received 1 ml/kg isotonic saline; AF group: received 1 ml/kg induction mixture of ACh/CaCl2 (60 µg ACh and 10 mg CaCl2 per ml); EMPA group: received 30 mg/kg EMPA; AF + EMPA10 group: received the induction mixture concurrent with 10 mg/kg EMPA; AF + EMPA30 group: received the induction mixture concurrent with 30 mg/kg EMPA. Our results showed that EMPA administration inhibited the AF-related electrocardiographic abnormalities and decreased the serum brain natriuretic peptide levels. EMPA treatment maintained the cardiac redox balance, as indicated by reduced levels of the lipid peroxidation biomarker malonaldehyde while enhancing the antioxidant glutathione levels. Moreover, EMPA markedly repressed ACh/CaCl2-induced C-reactive protein, tumor necrosis factor, and interleukin-6 production. Interestingly, EMPA administration strongly suppressed cardiac transforming growth factor beta1, collagen type I, and alpha-smooth muscle actin expression levels in the AF rats. These results were consistent with our histopathological findings, which revealed the ameliorative effect of EMPA on AF-induced inflammatory and fibrotic lesions. Mechanistically, EMPA dose-dependently downregulated nuclear factor-kappa B (NF-κB) and hypoxia-inducible factor (HIF)-1α expressions. Besides, it attenuated the pro-apoptotic active caspase-3 while augmenting the anti-apoptotic B-cell lymphoma 2 expressions. Furthermore, EMPA dose-dependently suppressed cardiac phosphatidylinositol 3-kinase (PI3K)/Akt signaling. In conclusion, this study demonstrates that EMPA intervention, within AF induction, protects against ACh/CaCl2-induced AF in rats, exerting powerful antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic effects. These effects are mainly mediated through the targeting of the NF-κB/HIF-1α regulatory axis in a dose-dependent manner.

PMID:39437485 | DOI:10.1016/j.intimp.2024.113403

Naunyn Schmiedebergs Arch Pharmacol. 2024 Oct 22. doi: 10.1007/s00210-024-03539-0. Online ahead of print.

ABSTRACT

Liver diseases represent a worldwide health problem accountable for two million deaths per year. Oxidative stress is critical for the development of these diseases. N-acetyl cysteine (NAC) is effective in preventing liver damage, both in experimental and clinical studies, and evidence has shown that the pharmacodynamic mechanisms of NAC are related to its antioxidant nature and ability to modulate key signaling pathways. Here, we provide a comprehensive description of the beneficial effects of NAC in the treatment of liver diseases, addressing the first evidence of its role as a scavenger and precursor of reduced glutathione, along with studies showing its immunomodulatory action, as well as the ability of NAC to modulate epigenetic hallmarks. We searched the PubMed database using the following keywords: oxidative stress, liver disease, epigenetics, antioxidants, NAC, and antioxidant therapies. There was no time limit to gather all available information on the subject. NAC has shown efficacy in treating liver damage, exerting mechanisms of action different from those of free radical scavengers. Like different antioxidant therapies, its effectiveness and safety are related to the administered dose; therefore, designing new pharmacological formulations for this drug is imperative to achieve an adequate response. Finally, there is still much to explore regarding its effect on epigenetic marker characteristics of liver damage, turning it into a drug with broad therapeutic potential. According to the literature reviewed, NAC could be an appropriate option in clinical studies related to hepatic injury and, in the future, a repurposing alternative for treating liver diseases.

PMID:39436429 | DOI:10.1007/s00210-024-03539-0

Invest Ophthalmol Vis Sci. 2024 Oct 1;65(12):32. doi: 10.1167/iovs.65.12.32.

ABSTRACT

PURPOSE: Keratoconus (KC) is a corneal disorder with complex etiology, apparently involving both genetic and environmental factors, characterized by progressive thinning and protrusion of the cornea. We aimed to identify novel genetic regions associated with KC susceptibility, elucidate relevant genes for disease development, and explore the translational implications for therapeutic intervention and risk assessment.

METHODS: We conducted a genome-wide association study (GWAS) that integrated previously published data with newly generated genotyping data from an independent European cohort. To evaluate the clinical translation of our results, we performed functional annotation, gene prioritization, polygenic risk score (PRS), and drug repositioning analyses.

RESULTS: We identified two novel genetic loci associated with KC, with rs2806689 and rs807037 emerging as lead variants (P = 1.71E-08, odds ratio [OR] = 0.88; P = 1.93E-08, OR = 1.16, respectively). Most importantly, we identified 315 candidate genes influenced by confirmed KC-associated variants. Among these, MINK1 was found to play a pivotal role in KC pathogenesis through the WNT signaling pathway. Moreover, we developed a PRS model that successfully differentiated KC patients from controls (P = 7.61E-16; area under the curve = 0.713). This model has the potential to identify individuals at high risk for developing KC, which could be instrumental in early diagnosis and management. Additionally, our drug repositioning analysis identified acetylcysteine as a potential treatment option for KC, opening up new avenues for therapeutic intervention.

CONCLUSIONS: Our study provides valuable insights into the genetic and molecular basis of KC, offering new targets for therapy and highlighting the clinical utility of PRS models in predicting disease risk.

PMID:39436372 | DOI:10.1167/iovs.65.12.32

Mater Today Bio. 2024 Oct 5;29:101285. doi: 10.1016/j.mtbio.2024.101285. eCollection 2024 Dec.

ABSTRACT

Inflammatory osteolysis poses a significant worldwide threat to public health. However, current monotherapies, which target either the prevention of the inflammatory response or the attenuation of osteoclast (OC) formation, have limited efficacy due to the complexity of the bone immune system being overlooked. Herein, by means of modifying salmon calcitonin (sCT), a multifunctional nano-system (AuNDs-sCT) was designed to synergistically inhibit OC differentiation and reverse the inflammatory microenvironment against inflammatory osteolysis. On the one hand, AuNDs-sCT effectively restrained OC differentiation by binding to the calcitonin receptors on the surface of OC precursors, resulting in the down-regulation of OC-specific genes and proteins. The targeted capacity of AuNDs-sCT provided a more durable and precise therapeutic effect. On the other hand, AuNDs-sCT exhibited antioxidant and anti-inflammatory effects, which regulated the polarization "switch" from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype in macrophages by the inhibition of NF-κB p65 phosphorylation, thereby effectively reversed the local inflammatory microenvironment. Additionally, AuNDs-sCT served as a promising fluorescent probe, enabling real-time visualization of the therapeutic process. This capability is expected to optimize drug administration and evaluate therapeutic effects. In summary, by inhibiting OC differentiation and reprogramming macrophages, AuNDs-sCT successfully realized drug repurposing and achieved the "one arrow two eagles" therapeutic strategy, which offers a synergistic and effective treatment option for the clinical management of inflammatory osteolysis.

PMID:39435372 | PMC:PMC11492609 | DOI:10.1016/j.mtbio.2024.101285

Sci Rep. 2024 Oct 21;14(1):24717. doi: 10.1038/s41598-024-75431-z.

ABSTRACT

Alzheimer's disease (AD) poses a major challenge due to its impact on the elderly population and the lack of effective early diagnosis and treatment options. In an effort to address this issue, a study focused on identifying potential biomarkers and therapeutic agents for AD was carried out. Using RNA-Seq data from AD patients and healthy individuals, 12 differentially expressed genes (DEGs) were identified, with 9 expressing upregulation (ISG15, HRNR, MTATP8P1, MTCO3P12, DTHD1, DCX, ST8SIA2, NNAT, and PCDH11Y) and 3 expressing downregulation (LTF, XIST, and TTR). Among them, TTR exhibited the lowest gene expression profile. Interestingly, functional analysis tied TTR to amyloid fiber formation and neutrophil degranulation through enrichment analysis. These findings suggested the potential of TTR as a diagnostic biomarker for AD. Additionally, druggability analysis revealed that the FDA-approved drug Levothyroxine might be effective against the Transthyretin protein encoded by the TTR gene. Molecular docking and dynamics simulation studies of Levothyroxine and Transthyretin suggested that this drug could be repurposed to treat AD. However, additional studies using in vitro and in vivo models are necessary before these findings can be applied in clinical applications.

PMID:39433822 | DOI:10.1038/s41598-024-75431-z

Microb Pathog. 2024 Oct 19:107046. doi: 10.1016/j.micpath.2024.107046. Online ahead of print.

ABSTRACT

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, is a serious health hazard, characterized by tuberculous granuloma formation, which may facilitate bacterial survival. At the same time, the identification of multidrug-resistant and extremely drug-resistant Mtb strains, and the progressive accumulation of mutations in biological targets of frontline antimicrobials, has made TB treatments more difficult. Therefore, new and rapid drug development for TB is warranted. Recently, drug repurposing has received considerable attention. In this study, we applied the anticancer drug degarelix to anti-TB research and found that it inhibits mycobacteria survival and pathological damage in Mycobacterium marinum-infected zebrafish and Mtb-infected mice. Supplementation of degarelix matched the bactericidal activities of rifampicin (RFP) toward M. marinum in zebrafish. Mechanistically, degarelix significantly increased interferon (IFN)-γ levels in M. marinum-infected zebrafish. Degarelix had no direct anti-mycobacterial activity in vitro but significantly reduced the survival of H37Rv in macrophages. The effect of degarelix could be reversed by 3-methyladenine (3-MA), which inhibits the class III phosphatidylinositol (PI) 3 kinase required for autophagy initiation. However, no effect on later steps in autophagy could be detected. Our findings demonstrate the potential of degarelix on limiting mycobacterial survival and granuloma formation, which may generate novel TB therapeutics.

PMID:39433139 | DOI:10.1016/j.micpath.2024.107046

Pharmacol Rep. 2024 Oct 21. doi: 10.1007/s43440-024-00662-w. Online ahead of print.

ABSTRACT

Metronomic chemotherapy (MC), long-term continuous administration of anticancer drugs, is gaining attention as an alternative to the traditional maximum tolerated dose (MTD) chemotherapy. By combining MC with other treatments, the therapeutic efficacy is enhanced while minimizing toxicity. MC employs multiple mechanisms, making it a versatile approach against various cancers. However, drug resistance limits the long-term effectiveness of MC, necessitating ongoing development of anticancer drugs. Traditional drug discovery is lengthy and costly due to processes like target protein identification, virtual screening, lead optimization, and safety and efficacy evaluations. Drug repurposing (DR), which screens FDA-approved drugs for new uses, is emerging as a cost-effective alternative. Both experimental and computational methods, such as protein binding assays, in vitro cytotoxicity tests, structure-based screening, and several types of association analyses (Similarity-Based, Network-Based, and Target Gene), along with retrospective clinical analyses, are employed for virtual screening. This review covers the mechanisms of MC, its application in various cancers, DR strategies, examples of repurposed drugs, and the associated challenges and future directions.

PMID:39432183 | DOI:10.1007/s43440-024-00662-w

Chem Biodivers. 2024 Oct 21:e202401561. doi: 10.1002/cbdv.202401561. Online ahead of print.

ABSTRACT

The investigation of new drugs is slow and costly. Drug repositioning, like with Hydralazine (HDZ), an old antihypertensive, can accelerate the process. HDZ and its hydrazonic derivatives exhibit diverse biological activities, promising for new drugs. This review explores HDZ's repositioning potential and its derivatives' applications in various biological activities. It identified 70 relevant articles through database searches. HDZ shows potential in neurology, oncology, nephrology, and gynecology, with clinical trials up to Phase III. Hydralazine-valproate, marketed in Mexico, proves effective in combination with chemotherapy. Hydrazonic derivatives offer broad applications in medicine. Studying their structure-activity relationship can enhance efficacy. This review summarizes their properties and pharmacological activities succinctly.

PMID:39429053 | DOI:10.1002/cbdv.202401561

Chem Biol Interact. 2024 Oct 18:111281. doi: 10.1016/j.cbi.2024.111281. Online ahead of print.

ABSTRACT

Common antimalarials such as artemisinins, chloroquine and their derivatives also possess potent anti-inflamantory, antiviral and anticancer properties. In the search for new therapeutics to combat difficult-to-treat pancreatic carcinomas, we unveiled that 4-aminoquinoline derivatives, with significant antiplasmodial properties and a great safety profile in vivo, have remarkable anticancer activity against pancreatic ductal adenocarcinoma (PDAC) and considerable efficacy in the xenograft model in vivo. The aim of the present study was to further investigate anticancer properties of these compounds in a drug-repurposing manner. The compounds showed profound cytotoxic effects at nanomolar to low micromolar concentration in 2D cultured cells (in vitro) and in the zebrafish PDAC xenograft model (in vivo). A deeper insight into their mechanisms of cytotoxic action showed these compounds induce apoptosis while increasing reactive oxygen species levels along with autophagy inhibition. Additional investigation of the autophagy modulation proved that tested quinoline derivatives cause P62 and LC3-II accumulation in PDAC cells alongside lysosomal alkalinization. Further, in vivo toxicity studies in the zebrafish model showed low toxicity without developmental side effects of the investigated 4-aminoquinolines, while the applied compounds effectively inhibited tumor growth and prevented the metastasis of xenografted pancreatic cells. Taken together, these results highlight the 4-aminoquinolines as privileged structures that ought to be investigated further for potential application in pancreatic carcinoma treatment.

PMID:39428053 | DOI:10.1016/j.cbi.2024.111281