Biotechnol Appl Biochem. 2021 Apr 1. doi: 10.1002/bab.2159. Online ahead of print.

ABSTRACT

The emergence and rapid spreading of novel SARS-CoV-2 across the globe represent an imminent threat to public health. Novel anti-viral therapies are urgently needed to overcome this pandemic. Given the significant role of the main protease of Covid-19 for virus replication, we performed a drug repurposing study using recently deposited main protease structure, 6LU7. For instance, pharmacophore- and e-pharmacophore-based hypotheses such as AARRH and AARR respectively were developed using available small molecule inhibitors and utilized in the screening of DrugBank repository. Further, hierarchical docking protocol was implemented with the support of Glide algorithm. The resultant compounds were then examined for its binding free energy against main protease of Covid-19 by means of Prime-MM/GBSA algorithm. Most importantly, machine learning based AutoQSAR algorithm was used to predict the anti-viral activities of resultant compounds. The hit molecules were also examined for its drug-likeness and its toxicity parameters through QikProp algorithm. Finally, the hit compounds activity against main protease was validated using molecular dynamic simulation studies. Overall, the present analysis yielded two potential inhibitors (DB02986 and DB08573) that are predicted to bind with the main protease of Covid-19 better than currently used drug molecules such as N3 (co-crystallized native ligand), Lopinavir and Ritonavir. This article is protected by copyright. All rights reserved.

PMID:33797130 | DOI:10.1002/bab.2159

Mol Biol Rep. 2021 Apr 1. doi: 10.1007/s11033-021-06318-9. Online ahead of print.

ABSTRACT

Increased deaths caused due to pancreatic cancer (PC) is drawing much attention towards an immediate need for therapeutics that could possibly control this disease and increase the patients' survival rate. Despite the long list of well-established chemotherapeutic drugs in several cancers none have proved to be efficient against PC, and the increasing chemoresistance to the gold standard drug gemcitabine calls a need to search for solutions in other categories of drug. To the rescue, antifungals have shown themselves to be effective against PC and can increase gemcitabine sensitivity against PC. In this mini-review, we reported how antifungals have targeted PC and helped to reduce its lethality. Additionally, it is emphasized that how the antifungals show new mechanisms that could be triggered by using either monotherapy or combination therapy of these antifungals with chemotherapeutic drugs in PC. Moreover it shows an approach of using other drugs with possible same or other mechanism to know their effect on PC.

PMID:33796989 | DOI:10.1007/s11033-021-06318-9

Nat Mach Intell. 2021 Mar;3(3):247-257. doi: 10.1038/s42256-020-00285-9. Epub 2021 Feb 1.

ABSTRACT

Phenotype-based compound screening has advantages over target-based drug discovery, but is unscalable and lacks understanding of mechanism. Chemical-induced gene expression profile provides a mechanistic signature of phenotypic response. However, the use of such data is limited by their sparseness, unreliability, and relatively low throughput. Few methods can perform phenotype-based de novo chemical compound screening. Here, we propose a mechanism-driven neural network-based method DeepCE, which utilizes graph neural network and multi-head attention mechanism to model chemical substructure-gene and gene-gene associations, for predicting the differential gene expression profile perturbed by de novo chemicals. Moreover, we propose a novel data augmentation method which extracts useful information from unreliable experiments in L1000 dataset. The experimental results show that DeepCE achieves superior performances to state-of-the-art methods. The effectiveness of gene expression profiles generated from DeepCE is further supported by comparing them with observed data for downstream classification tasks. To demonstrate the value of DeepCE, we apply it to drug repurposing of COVID-19, and generate novel lead compounds consistent with clinical evidence. Thus, DeepCE provides a potentially powerful framework for robust predictive modeling by utilizing noisy omics data and screening novel chemicals for the modulation of a systemic response to disease.

PMID:33796820 | PMC:PMC8009091 | DOI:10.1038/s42256-020-00285-9

Ther Adv Drug Saf. 2021 Mar 15;12:2042098621998876. doi: 10.1177/2042098621998876. eCollection 2021.

NO ABSTRACT

PMID:33796258 | PMC:PMC7968020 | DOI:10.1177/2042098621998876

Bioinform Biol Insights. 2021 Mar 15;15:11779322211002168. doi: 10.1177/11779322211002168. eCollection 2021.

ABSTRACT

The application of bioinformatics to vaccine research and drug discovery has never been so essential in the fight against infectious diseases. The greatest combat of the 21st century against a debilitating disease agent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus discovered in Wuhan, China, December 2019, has piqued an unprecedented usage of bioinformatics tools in deciphering the molecular characterizations of infectious pathogens. With the viral genome data of SARS-COV-2 been made available barely weeks after the reported outbreak, bioinformatics platforms have become an all-time critical tool to gain time in the fight against the disease pandemic. Before the outbreak, different platforms have been developed to explore antigenic epitopes, predict peptide-protein docking and antibody structures, and simulate antigen-antibody reactions and lots more. However, the advent of the pandemic witnessed an upsurge in the application of these pipelines with the development of newer ones such as the Coronavirus Explorer in the development of efficacious vaccines, drug repurposing, and/or discovery. In this review, we have explored the various pipelines available for use, their relevance, and limitations in the timely development of useful therapeutic candidates from genomic data knowledge to clinical therapy.

PMID:33795932 | PMC:PMC7968009 | DOI:10.1177/11779322211002168

Genomics Proteomics Bioinformatics. 2021 Mar 29:S1672-0229(21)00075-9. doi: 10.1016/j.gpb.2020.05.006. Online ahead of print.

ABSTRACT

Current FDA-approved kinase inhibitors cause diverse adverse effects, some of which are due to the mechanism-independent effects of these drugs. Identifying these mechanism-independent interactions could improve drug safety and support drug repurposing. We have developed iDTPnd (integrated Drug Target Predictor with negative dataset), a computational approach for large-scale discovery of novel targets for known drugs. For a given drug, we construct a positive and a negative structural signature that captures the weakly conserved structural features of drug binding sites. To facilitate assessment of unintended targets, iDTPnd also provides a docking-based interaction score and its statistical significance. We were able to confirm the interaction of sorafenib, imatinib, dasatinib, sunitinib, and pazopanib with their known targets at a sensitivity and specificity of 52% and 55%, respectively. We have validated 10 predicted novel targets by using in vitro experiments. Our results suggest that proteins other than kinases, such as nuclear receptors, cytochrome P450, or MHC Class I molecules can also be physiologically relevant targets of kinase inhibitors. Our method is general and broadly applicable for the identification of protein-small molecule interactions, when sufficient drug-target 3D data are available. The code for constructing the structural signature is available at https://sfb.kaust.edu.sa/Documents/iDTP.zip.

PMID:33794377 | DOI:10.1016/j.gpb.2020.05.006

J Biochem. 2021 Apr 1:mvab045. doi: 10.1093/jb/mvab045. Online ahead of print.

ABSTRACT

Given the huge cost, long research and development (R&D) time and uncertain side effects of discovering new drugs, drug repositioning of those approved to treat diseases clinically as new drugs for other pathological conditions, especially cancers, is a potential alternative strategy. Disulfiram (DSF), an old drug used to treat alcoholism, has been found to exhibit anticancer activity and improve chemotherapeutic efficacy in cancers by an increasing number of studies. In addition, the combination of DSF and copper may be a more effective therapeutic strategy. In this study, we report the toxicity of the DSF/Cu complex to human osteosarcoma both in vitro and in vivo. DSF/Cu significantly inhibited the proliferation and clonogenicity of osteosarcoma cell lines. Furthermore, the generation of ROS was triggered by DSF/Cu, and cell arrest, autophagy and apoptosis were induced in a ROS-dependent manner. The underlying mechanism of this process was explored, and DSF/Cu may mainly inhibit osteosarcoma by inducing apoptosis by activating the ROS/JNK pathway. DSF/Cu also inhibited osteosarcoma growth in a xenograft model with low levels of organ-related toxicities. These results suggest that the DSF/Cu complex could be an efficient and safe option for the treatment of osteosarcoma in the clinic.

PMID:33792698 | DOI:10.1093/jb/mvab045

Future Oncol. 2021 Apr 1. doi: 10.2217/fon-2020-0834. Online ahead of print.

ABSTRACT

Aims: Comparison of efficacy, safety and sedation between two doses of olanzapine in the control of chemotherapy-induced nausea and vomiting (CINV). Patients & methods: A prospective, randomized, double-blind, controlled study was conducted, enrolling 68 patients receiving a single-day cycle of high and moderately emetogenic chemotherapy. Patients received either of olanzapine 5 mg or 10 mg from day 1 through 3 in addition to ondansetron and dexamethasone. Control of CINV, nausea, sedation, quality of life (QoL) and adverse events were compared. Results: Nausea, emesis control and improvement of QoL were similar in both groups. Sedation severity was 133% higher with 10 mg olanzapine. Conclusions: Lower dose olanzapine is effective to control CINV with significantly reduced sedation.

PMID:33792376 | DOI:10.2217/fon-2020-0834

Sci Rep. 2021 Mar 31;11(1):7307. doi: 10.1038/s41598-021-86712-2.

ABSTRACT

Outcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.

PMID:33790352 | DOI:10.1038/s41598-021-86712-2

Biol Pharm Bull. 2021;44(4):550-556. doi: 10.1248/bpb.b20-00889.

ABSTRACT

We previously reported a screening method for caloric restriction mimetics (CRM), a group of plant-derived compounds capable of inducing good health and longevity. In the present study, we explored the possibility of using this method to screen CRM drugs for drug repositioning. The method, T-cell activation-inhibitory assay, is based on inductive logic. Most of CRM such as resveratrol have been reported to suppress T-cell activation and have anti-inflammatory functions. Here, we assessed the activity of 12 antiallergic drugs through T-cell activation-inhibitory assay and selected four that showed the lowest IC50 values-ibudilast (IC50 0.97 µM), azelastine (IC50 7.2 µM), epinastine (IC50 16 µM), and amlexanox (IC50 33 µM)-for further investigation. Because azelastine showed high cytotoxicity, we selected only the remaining three drugs to study their biological functions. We found that all the three drugs suppressed the expression of interleukin (IL)-6, an inflammatory cytokine, in lipopolysaccharide-treated macrophage cells, with ibudilast being the strongest suppressor. Ibudilast also suppressed the secretion of another inflammatory cytokine, tumor necrosis factor (TNF)-α, and the expression of an inflammatory enzyme, cyclooxygenase-2, in the cells. These results suggest that T-cell activation-inhibitory assay can be used to screen potential CRM drugs having anti-inflammatory functions for the purpose of drug repositioning.

PMID:33790105 | DOI:10.1248/bpb.b20-00889

J Immunoassay Immunochem. 2021 Mar 31:1-20. doi: 10.1080/15321819.2021.1904414. Online ahead of print.

ABSTRACT

In this review, we present an elaborate account of coronavirus in context to Covid-19 focusing on its origin, genome, life cycle, and immunology with a basic understanding of the disease and its cause. Further, the transmission, prevention and advances in therapeutics have also been discussed anticipating the possible outcomes in the near future. Moreover, the recently emerged unconventional approaches to this viral disease like drug repurposing, plasma therapy, nasal spray, and other preventive measures worldwide are studied for a long-term impact and relevance. Hence, this account on coronavirus and the ongoing pandemic serves a purpose of spreading awareness and to pass on relevant knowledge for a better chance to combat such unfortunate health crisis in future.

PMID:33788668 | DOI:10.1080/15321819.2021.1904414

Database (Oxford). 2021 Mar 31;2021:baab017. doi: 10.1093/database/baab017.

ABSTRACT

Understanding the underlying molecular and structural similarities between seemingly heterogeneous sets of drugs can aid in identifying drug repurposing opportunities and assist in the discovery of novel properties of preclinical small molecules. A wealth of information about drug and small molecule structure, targets, indications and side effects; induced gene expression signatures; and other attributes are publicly available through web-based tools, databases and repositories. By processing, abstracting and aggregating information from these resources into drug set libraries, knowledge about novel properties of drugs and small molecules can be systematically imputed with machine learning. In addition, drug set libraries can be used as the underlying database for drug set enrichment analysis. Here, we present Drugmonizome, a database with a search engine for querying annotated sets of drugs and small molecules for performing drug set enrichment analysis. Utilizing the data within Drugmonizome, we also developed Drugmonizome-ML. Drugmonizome-ML enables users to construct customized machine learning pipelines using the drug set libraries from Drugmonizome. To demonstrate the utility of Drugmonizome, drug sets from 12 independent SARS-CoV-2 in vitro screens were subjected to consensus enrichment analysis. Despite the low overlap among these 12 independent in vitro screens, we identified common biological processes critical for blocking viral replication. To demonstrate Drugmonizome-ML, we constructed a machine learning pipeline to predict whether approved and preclinical drugs may induce peripheral neuropathy as a potential side effect. Overall, the Drugmonizome and Drugmonizome-ML resources provide rich and diverse knowledge about drugs and small molecules for direct systems pharmacology applications. Database URL: https://maayanlab.cloud/drugmonizome/.

PMID:33787872 | DOI:10.1093/database/baab017

Rev Bras Parasitol Vet. 2021 Mar 26;30(1):e022120. doi: 10.1590/S1984-29612021006. eCollection 2021.

ABSTRACT

Neospora caninum is an apicomplexan parasite that causes abortion in cattle, resulting in significant economic losses. There is no commercial treatment for neosporosis, and drug repositioning is a fast strategy to test possible candidates against N. caninum. In this article, we describe the effects of atovaquone, chloroquine, quinine, primaquine and tetracycline on N. caninum proliferation. The IC50 concentrations in N. caninum were compared to the current information based on previous studies for Plasmodium and Toxoplasma gondii, correlating to the described mechanisms of action of each tested drug. The inhibitory patterns indicate similarities and differences among N. caninum, Plasmodium and T. gondii. For example, atovaquone demonstrates high antiparasitic activity in all the analyzed models, while chloroquine does not inhibit N. caninum. On the other hand, tetracycline is effective against Plasmodium and N. caninum, despite its low activity in T. gondii models. The repurposing of antimalarial drugs in N. caninum is a fast and inexpensive way to develop novel formulations using well-established compounds.

PMID:33787719 | DOI:10.1590/S1984-29612021006

Mol Inform. 2021 Mar 30. doi: 10.1002/minf.202000187. Online ahead of print.

ABSTRACT

Considering the urgent need for novel therapeutics in ongoing COVID-19 pandemic, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we designed an integrative in silico drug repurposing approach for rapid selection of potential candidates against SARS-CoV-2 Main Protease (Mpro ). To screen FDA-approved drugs, we implemented structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data mining analysis of drug-gene-COVID-19 association. Through presented approach, we selected the most promising FDA approved drugs for further COVID-19 drug development campaigns and analysed them in context of available experimental data. To the best of our knowledge, this is unique in silico study which integrates structure-based molecular modeling of Mpro inhibitors with predictions of their tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.

PMID:33787066 | DOI:10.1002/minf.202000187

Adv Ther (Weinh). 2021 Feb 22:2000224. doi: 10.1002/adtp.202000224. Online ahead of print.

ABSTRACT

SARS-CoV-2 caused the emerging epidemic of coronavirus disease in 2019 (COVID-19). To date, there are more than 82.9 million confirmed cases worldwide, there is no clinically effective drug against SARS-CoV-2 infection. The conserved properties of the membrane fusion domain of the spike (S) protein across SARS-CoV-2 make it a promising target to develop pan-CoV therapeutics. Herein, two clinically approved drugs, Itraconazole (ITZ) and Estradiol benzoate (EB), are found to inhibit viral entry by targeting the six-helix (6-HB) fusion core of SARS-CoV-2 S protein. Further studies shed light on the mechanism that ITZ and EB can interact with the heptad repeat 1 (HR1) region of the spike protein, to present anti-SARS-CoV-2 infections in vitro, indicating they are novel potential therapeutic remedies for COVID-19 treatment. Furthermore, ITZ shows broad-spectrum activity targeting 6-HB in the S2 subunit of SARS-CoV and MERS-CoV S protein, inspiring that ITZ have the potential for development as a pan-coronavirus fusion inhibitor.

PMID:33786369 | PMC:PMC7994988 | DOI:10.1002/adtp.202000224

ACS Chem Neurosci. 2021 Mar 29. doi: 10.1021/acschemneuro.1c00091. Online ahead of print.

ABSTRACT

Accumulating evidence have shown a strong pathological correlation between cardiovascular disease (CVD) and Type II diabetes (T2D), both of which share many common risk factors (e.g., hyperglycemia, hypertension, hypercoagulability, and dyslipidemia) and mutually contribute to each other. Driven by such strong CVD-T2D correlation and marginal benefits from drug development for T2D, here we proposed to repurpose a CVD drug of cloridarol as human islet amyloid peptide (hIAPP) inhibitor against its abnormal misfolding and aggregation, which is considered as a common and critical pathological event in T2D. To this end, we investigated the inhibition activity of cloridarol on the aggregation and toxicity of hIAPP1-37 using combined experimental and computational approaches. Collective experimental data from ThT, AFM, and CD demonstrated the inhibition ability of cloridarol to prevent hIAPP aggregation from its monomeric and oligomeric states, leading to the overall reduction of hIAPP fibrils up to 57% at optimal conditions. MTT and LDH cell assays also showed that cloridarol can also effectively increase cell viability by 15% and decrease cell apoptosis by 28%, confirming its protection of islet β-cells from hIAPP-induced cell toxicity. Furthermore, comparative molecular dynamics simulations revealed that cloridarol was preferentially bound to the C-terminal β-sheet region of hIAPP oligomers through a combination of hydrophobic interactions, π-π stacking, and hydrogen bonding. Such multiple site bindings allowed cloridarol to disturb hIAPP structures, reduce β-sheet content, and block the lateral association pathway of hIAPP aggregates, thus explaining experimental findings. Different from other single-target hIAPP inhibitors, cloridarol is unique in that it works as both a CVD drug and hIAPP inhibitor, which can be used as a viable structural template (especially for benzofuran) for the further development of cloridarol-based or benzofuran-based inhibitors of amyloid proteins.

PMID:33780229 | DOI:10.1021/acschemneuro.1c00091

ACS Omega. 2021 Mar 10;6(11):7454-7468. doi: 10.1021/acsomega.0c05996. eCollection 2021 Mar 23.

ABSTRACT

Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a newly identified virus that has resulted in over 2.5 million deaths globally and over 116 million cases globally in March, 2021. Small-molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola viruses and demonstrated activity against SARS-CoV-2 in vivo. Most notably, the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small-molecule drugs that are active against Ebola viruses (EBOVs) would appear a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone, and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg viruses in vitro in HeLa cells and mouse-adapted EBOV in mice in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7, and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We used microscale thermophoresis to test the binding of these molecules to the spike protein, and tilorone and pyronaridine bind to the spike receptor binding domain protein with K d values of 339 and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 observed in A549-ACE2 cells. We also provide novel insights into the mechanism of these compounds which is likely lysosomotropic.

PMID:33778258 | PMC:PMC7992063 | DOI:10.1021/acsomega.0c05996

Biochem Biophys Rep. 2021 Mar 15;26:100943. doi: 10.1016/j.bbrep.2021.100943. eCollection 2021 Jul.

ABSTRACT

The pathogenesis of Alzheimer's disease (AD) is correlated with the misfolding and aggregation of amyloid-beta protein (Aβ). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aβ, modulate the process of aggregation and supress its cytotoxic effect, initially via a reversible binding interaction, followed by covalent bonding between specific functional groups (nucleophiles) within the Aβ peptide and the beta-lactam ring. Mass spectrometry and computational docking supported covalent modification of Aβ by BP. BP was found to inhibit aggregation of Aβ as revealed by the Thioflavin T (ThT) fluorescence assay and atomic force microscopy (AFM). In addition, BP treatment was found to have a cytoprotective activity against Aβ-induced cell cytotoxicity as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell toxicity assay. The specific interaction of BP with Aβ suggests the possibility of structure-based drug design, leading to the identification of new drug candidates against AD. Moreover, good pharmacokinetics of beta-lactam antibiotics and safety on long-time use make them valuable candidates for drug repurposing towards neurological disorders such as AD.

PMID:33778168 | PMC:PMC7985693 | DOI:10.1016/j.bbrep.2021.100943

Front Cell Infect Microbiol. 2021 Mar 11;11:633194. doi: 10.3389/fcimb.2021.633194. eCollection 2021.

ABSTRACT

Parasitic infections contribute significantly to worldwide morbidity and mortality. Antibiotic treatment is essential for managing patients infected with these parasites since control is otherwise challenging and there are no vaccines available for prevention. However, new antimicrobial therapies are urgently needed as significant problems exist with current treatments such as drug resistance, limited options, poor efficacy, as well as toxicity. This situation is made worse by the challenges of drug discovery and development which is costly especially for non-profitable infectious diseases, time-consuming, and risky with a high failure rate. Drug repurposing which involves finding new use for existing drugs may help to more rapidly identify therapeutic candidates while drastically cutting costs of drug research and development. In this perspective article, we discuss the importance of drug repurposing, review disulfiram pharmacology, and highlight emerging data that supports repurposing disulfiram as an anti-parasitic, exemplified by the major diarrhea-causing parasite Entamoeba histolytica.

PMID:33777846 | PMC:PMC7991622 | DOI:10.3389/fcimb.2021.633194

Front Oncol. 2021 Mar 11;11:617937. doi: 10.3389/fonc.2021.617937. eCollection 2021.

ABSTRACT

Glucocorticoids (GCs) are a central component of multi-drug treatment protocols against T and B acute lymphoblastic leukemia (ALL), which are used intensively during the remission induction to rapidly eliminate the leukemic blasts. The primary response to GCs predicts the overall response to treatment and clinical outcome. In this review, we have critically analyzed the available data on the effects of GCs on sensitive and resistant leukemic cells, in order to reveal the mechanisms of GC resistance and how these mechanisms may determine a poor outcome in ALL. Apart of the GC resistance, associated with a decreased expression of receptors to GCs, there are several additional mechanisms, triggered by alterations of different signaling pathways, which cause the metabolic reprogramming, with an enhanced level of glycolysis and oxidative phosphorylation, apoptosis resistance, and multidrug resistance. Due to all this, the GC-resistant ALL show a poor sensitivity to conventional chemotherapeutic protocols. We propose pharmacological strategies that can trigger alternative intracellular pathways to revert or overcome GC resistance. Specifically, we focused our search on drugs, which are already approved for treatment of other diseases and demonstrated anti-ALL effects in experimental pre-clinical models. Among them are some "truly" re-purposed drugs, which have different targets in ALL as compared to other diseases: cannabidiol, which targets mitochondria and causes the mitochondrial permeability transition-driven necrosis, tamoxifen, which induces autophagy and cell death, and reverts GC resistance through the mechanisms independent of nuclear estrogen receptors ("off-target effects"), antibiotic tigecycline, which inhibits mitochondrial respiration, causing energy crisis and cell death, and some anthelmintic drugs. Additionally, we have listed compounds that show a classical mechanism of action in ALL but are not used still in treatment protocols: the BH3 mimetic venetoclax, which inhibits the anti-apoptotic protein Bcl-2, the hypomethylating agent 5-azacytidine, which restores the expression of the pro-apoptotic BIM, and compounds targeting the PI3K-Akt-mTOR axis. Accordingly, these drugs may be considered for the inclusion into chemotherapeutic protocols for GC-resistant ALL treatments.

PMID:33777761 | PMC:PMC7991804 | DOI:10.3389/fonc.2021.617937