Pharmaceuticals

2023

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11 pages, 568 KiB

Open AccessArticle

Association between Fluoxetine Use and Overall Survival among Patients with Cancer Treated with PD-1/L1 Immunotherapy

by Joseph Magagnoli, Siddharth Narendran, Felipe Pereira, Tammy H. Cummings, James W. Hardin, S. Scott Sutton and Jayakrishna Ambati

Pharmaceuticals 2023, 16(5), 640; https://doi.org/10.3390/ph16050640 - 23 Apr 2023

Cited by 2 | Viewed by 3811

Abstract

Checkpoint inhibitors can be a highly effective antitumor therapy but only to a subset of patients, presumably due to immunotherapy resistance. Fluoxetine was recently revealed to inhibit the NLRP3 inflammasome, and NLRP3 inhibition could serve as a target for immunotherapy resistance. Therefore, we [...] Read more.

Checkpoint inhibitors can be a highly effective antitumor therapy but only to a subset of patients, presumably due to immunotherapy resistance. Fluoxetine was recently revealed to inhibit the NLRP3 inflammasome, and NLRP3 inhibition could serve as a target for immunotherapy resistance. Therefore, we evaluated the overall survival (OS) in patients with cancer receiving checkpoint inhibitors combined with fluoxetine. A cohort study was conducted among patients diagnosed with lung, throat (pharynx or larynx), skin, or kidney/urinary cancer treated with checkpoint inhibitor therapy. Utilizing the Veterans Affairs Informatics and Computing Infrastructure, patients were retrospectively evaluated during the period from October 2015 to June 2021. The primary outcome was overall survival (OS). Patients were followed until death or the end of the study period. There were 2316 patients evaluated, including 34 patients who were exposed to checkpoint inhibitors and fluoxetine. Propensity score weighted Cox proportional hazards demonstrated a better OS in fluoxetine-exposed patients than unexposed (HR: 0.59, 95% CI 0.371–0.936). This cohort study among cancer patients treated with checkpoint inhibitor therapy showed a significant improvement in the OS when fluoxetine was used. Because of this study’s potential for selection bias, randomized trials are needed to assess the efficacy of the association of fluoxetine or another anti-NLRP3 drug to checkpoint inhibitor therapy. Full article

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2022

Jump to: 2023, 2021, 2020, 2019, 2018, 2017

15 pages, 4991 KiB

Open AccessArticle

Long-Term Sleep Deprivation-Induced Myocardial Remodeling and Mitochondrial Dysfunction in Mice Were Attenuated by Lipoic Acid and N-Acetylcysteine

by Fei Song, Jiale Lin, Houjian Zhang, Yuli Guo, Yijie Mao, Zuguo Liu, Gang Li and Yan Wang

Pharmaceuticals 2023, 16(1), 51; https://doi.org/10.3390/ph16010051 - 29 Dec 2022

Cited by 3 | Viewed by 4008

Abstract

The impact of long-term sleep deprivation on the heart and its underlying mechanisms are poorly understood. The present study aimed to investigate the impact of chronic sleep deprivation (CSD) on the heart and mitochondrial function and explore an effective drug for treating CSD-induced [...] Read more.

The impact of long-term sleep deprivation on the heart and its underlying mechanisms are poorly understood. The present study aimed to investigate the impact of chronic sleep deprivation (CSD) on the heart and mitochondrial function and explore an effective drug for treating CSD-induced heart dysfunction. We used a modified method to induce CSD in mice; lipoic acid (LA) and N-acetylcysteine (NAC) were used to treat CSD mice. Echocardiography, hematoxylin-eosin (H&E) staining, Sirius red staining, and immunohistochemistry were used to determine heart function and cardiac fibrosis. The serum levels of brain natriuretic peptide (BNP), superoxide Dismutase (SOD), micro malondialdehyde (MDA), and glutathione (GSH) were measured to determine cardiovascular and oxidative stress-related damage. Transmission electron microscopy was used to investigate mitochondrial damage. RNA-seq and Western blotting were used to explore related pathways. We found that the left ventricular ejection fraction (LVEF) and fraction shortening (LVFS) values were significantly decreased and myocardial hypertrophy was induced, accompanied by damaged mitochondria, elevated reactive oxygen species (ROS), and reduced SOD levels. RNA-sequence analysis of the heart tissue showed that various differentially expressed genes in the metabolic pathway were enriched. Sirtuin 1 (Sirt1) and Glutathione S-transferase A3 (Gsta3) may be responsible for CSD-induced heart and mitochondrial dysfunction. Pharmacological inhibition of ROS by treating CSD mice with LA and NAC effectively reduced heart damage and mitochondrial dysfunction by regulating Sirt1 and Gsta3 expression. Our data contribute to understanding the pathways of CSD-induced heart dysfunction, and pharmacological targeting to ROS may represent a strategy to prevent CSD-induced heart damage. Full article

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2021

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23 pages, 1581 KiB

Open AccessReview

Ranolazine: An Old Drug with Emerging Potential; Lessons from Pre-Clinical and Clinical Investigations for Possible Repositioning

by Sarah Rouhana, Anne Virsolvy, Nassim Fares, Sylvain Richard and Jérôme Thireau

Pharmaceuticals 2022, 15(1), 31; https://doi.org/10.3390/ph15010031 - 25 Dec 2021

Cited by 13 | Viewed by 9693

Abstract

Ischemic heart disease is a significant public health problem with high mortality and morbidity. Extensive scientific investigations from basic sciences to clinics revealed multilevel alterations from metabolic imbalance, altered electrophysiology, and defective Ca²⁺/Na⁺ homeostasis leading to lethal arrhythmias. Despite the [...] Read more.

Ischemic heart disease is a significant public health problem with high mortality and morbidity. Extensive scientific investigations from basic sciences to clinics revealed multilevel alterations from metabolic imbalance, altered electrophysiology, and defective Ca²⁺/Na⁺ homeostasis leading to lethal arrhythmias. Despite the recent identification of numerous molecular targets with potential therapeutic interest, a pragmatic observation on the current pharmacological R&D output confirms the lack of new therapeutic offers to patients. By contrast, from recent trials, molecules initially developed for other fields of application have shown cardiovascular benefits, as illustrated with some anti-diabetic agents, regardless of the presence or absence of diabetes, emphasizing the clear advantage of “old” drug repositioning. Ranolazine is approved as an antianginal agent and has a favorable overall safety profile. This drug, developed initially as a metabolic modulator, was also identified as an inhibitor of the cardiac late Na⁺ current, although it also blocks other ionic currents, including the hERG/Ikr K⁺ current. The latter actions have been involved in this drug’s antiarrhythmic effects, both on supraventricular and ventricular arrhythmias (VA). However, despite initial enthusiasm and promising development in the cardiovascular field, ranolazine is only authorized as a second-line treatment in patients with chronic angina pectoris, notwithstanding its antiarrhythmic properties. A plausible reason for this is the apparent difficulty in linking the clinical benefits to the multiple molecular actions of this drug. Here, we review ranolazine’s experimental and clinical knowledge on cardiac metabolism and arrhythmias. We also highlight advances in understanding novel effects on neurons, the vascular system, skeletal muscles, blood sugar control, and cancer, which may open the way to reposition this “old” drug alone or in combination with other medications. Full article

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15 pages, 1096 KiB

Open AccessReview

SapC–DOPS as a Novel Therapeutic and Diagnostic Agent for Glioblastoma Therapy and Detection: Alternative to Old Drugs and Agents

by Ahmet Kaynak, Harold W. Davis, Subrahmanya D. Vallabhapurapu, Koon Y. Pak, Brian D. Gray and Xiaoyang Qi

Pharmaceuticals 2021, 14(11), 1193; https://doi.org/10.3390/ph14111193 - 20 Nov 2021

Cited by 1 | Viewed by 3408

Abstract

Glioblastoma multiforme (GBM), the most common type of brain cancer, is extremely aggressive and has a dreadful prognosis. GBM comprises 60% of adult brain tumors and the 5 year survival rate of GBM patients is only 4.3%. Standard-of-care treatment includes maximal surgical removal [...] Read more.

Glioblastoma multiforme (GBM), the most common type of brain cancer, is extremely aggressive and has a dreadful prognosis. GBM comprises 60% of adult brain tumors and the 5 year survival rate of GBM patients is only 4.3%. Standard-of-care treatment includes maximal surgical removal of the tumor in combination with radiation and temozolomide (TMZ) chemotherapy. TMZ is the “gold-standard” chemotherapy for patients suffering from GBM. However, the median survival is only about 12 to 18 months with this protocol. Consequently, there is a critical need to develop new therapeutic options for treatment of GBM. Nanomaterials have unique properties as multifunctional platforms for brain tumor therapy and diagnosis. As one of the nanomaterials, lipid-based nanocarriers are capable of delivering chemotherapeutics and imaging agents to tumor sites by enhancing the permeability of the compound through the blood–brain barrier, which makes them ideal for GBM therapy and imaging. Nanocarriers also can be used for delivery of radiosensitizers to the tumor to enhance the efficacy of the radiation therapy. Previously, high-atomic-number element-containing particles such as gold nanoparticles and liposomes have been used as radiosensitizers. SapC–DOPS, a protein-based liposomal drug comprising the lipid, dioleoylphosphatidylserine (DOPS), and the protein, saposin C (SapC), has been shown to be effective for treatment of a variety of cancers in small animals, including GBM. SapC–DOPS also has the unique ability to be used as a carrier for delivery of radiotheranostic agents for nuclear imaging and radiotherapeutic purposes. These unique properties make tumor-targeting proteo-liposome nanocarriers novel therapeutic and diagnostic alternatives to traditional chemotherapeutics and imaging agents. This article reviews various treatment modalities including nanolipid-based delivery and therapeutic systems used in preclinical and clinical trial settings for GBM treatment and detection. Full article

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16 pages, 1152 KiB

Open AccessReview

Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications

by Marina Caldara and Nelson Marmiroli

Pharmaceuticals 2021, 14(9), 915; https://doi.org/10.3390/ph14090915 - 10 Sep 2021

Cited by 25 | Viewed by 6596

Abstract

The spreading of antibiotic resistance is responsible annually for over 700,000 deaths worldwide, and the prevision is that this number will increase exponentially. The identification of new antimicrobial treatments is a challenge that requires scientists all over the world to collaborate. Developing new [...] Read more.

The spreading of antibiotic resistance is responsible annually for over 700,000 deaths worldwide, and the prevision is that this number will increase exponentially. The identification of new antimicrobial treatments is a challenge that requires scientists all over the world to collaborate. Developing new drugs is an extremely long and costly process, but it could be paralleled by drug repositioning. The latter aims at identifying new clinical targets of an “old” drug that has already been tested, approved, and even marketed. This approach is very intriguing as it could reduce costs and speed up approval timelines, since data from preclinical studies and on pharmacokinetics, pharmacodynamics, and toxicity are already available. Antidepressants and antipsychotics have been described to inhibit planktonic and sessile growth of different yeasts and bacteria. The main findings in the field are discussed in this critical review, along with the description of the possible microbial targets of these molecules. Considering their antimicrobial activity, the manuscript highlights important implications that the administration of antidepressants and antipsychotics may have on the gut microbiome. Full article

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19 pages, 2943 KiB

Open AccessArticle

Pitavastatin Is a Highly Potent Inhibitor of T-Cell Proliferation

by Linda Voss, Karina Guttek, Annika Reddig, Annegret Reinhold, Martin Voss, Luca Simeoni, Burkhart Schraven and Dirk Reinhold

Pharmaceuticals 2021, 14(8), 727; https://doi.org/10.3390/ph14080727 - 27 Jul 2021

Cited by 6 | Viewed by 3635

Abstract

Repositioning of approved drugs is an alternative time- and cost-saving strategy to classical drug development. Statins are 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitors that are usually used as cholesterol-lowering medication, and they also exhibit anti-inflammatory effects. In the present study, we observed that the [...] Read more.

Repositioning of approved drugs is an alternative time- and cost-saving strategy to classical drug development. Statins are 3-hydroxy-3-methylglutaryl-CoA (HMG CoA) reductase inhibitors that are usually used as cholesterol-lowering medication, and they also exhibit anti-inflammatory effects. In the present study, we observed that the addition of Pitavastatin at nanomolar concentrations inhibits the proliferation of CD3/CD28 antibody-stimulated human T cells of healthy donors in a dose-dependent fashion. The 50% inhibition of proliferation (IC50) were 3.6 and 48.5 nM for freshly stimulated and pre-activated T cells, respectively. In addition, Pitavastatin suppressed the IL-10 and IL-17 production of stimulated T cells. Mechanistically, we found that treatment of T cells with doses <1 µM of Pitavastatin induced hyperphosphorylation of ERK1/2, and activation of caspase-9, -3 and -7, thus leading to apoptosis. Mevalonic acid, cholesterol and the MEK1/2 inhibitor U0126 reversed this Pitavastatin-mediated ERK1/2 activation and apoptosis of T cells. In summary, our results suggest that Pitavastatin is a highly potent inhibitor of T-cell proliferation, which induces apoptosis via pro-apoptotic ERK1/2 activation, thus representing a potential repositioning candidate for the treatment of T-cell-mediated autoimmune diseases. Full article

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26 pages, 7880 KiB

Open AccessArticle

Conjugation of Diclofenac with Novel Oleanolic Acid Derivatives Modulate Nrf2 and NF-κB Activity in Hepatic Cancer Cells and Normal Hepatocytes Leading to Enhancement of Its Therapeutic and Chemopreventive Potential

by Maria Narożna, Violetta Krajka-Kuźniak, Barbara Bednarczyk-Cwynar, Małgorzata Kucińska, Robert Kleszcz, Jacek Kujawski, Hanna Piotrowska-Kempisty, Adam Plewiński, Marek Murias and Wanda Baer-Dubowska

Pharmaceuticals 2021, 14(7), 688; https://doi.org/10.3390/ph14070688 - 17 Jul 2021

Cited by 15 | Viewed by 4637

Abstract

Combining NSAIDs with conventional therapeutics was recently explored as a new strategy in cancer therapy. Our earlier studies showed that novel oleanolic acid oximes (OAO) conjugated with aspirin or indomethacin may enhance their anti-cancer potential through modulation of the Nrf2 and NF-κB signaling [...] Read more.

Combining NSAIDs with conventional therapeutics was recently explored as a new strategy in cancer therapy. Our earlier studies showed that novel oleanolic acid oximes (OAO) conjugated with aspirin or indomethacin may enhance their anti-cancer potential through modulation of the Nrf2 and NF-κB signaling pathways. This study focused on the synthesis and biological evaluation of four diclofenac (DCL)–OAO derivative conjugates in the context of these pathways’ modification and hepatic cells survival. Treatment with the conjugates 4d, 3-diclofenacoxyiminoolean-12-en-28-oic acid morpholide, and 4c, 3-diclofenacoxyiminoolean-12-en-28-oic acid benzyl ester significantly reduced cell viability in comparison to the DCL alone. In THLE-2, immortalized normal hepatocytes treated with these conjugates resulted in the activation of Nrf2 and increased expression in SOD-1 and NQO1, while the opposite effect was observed in the HepG2 hepatoma cells. In both cell lines, reduced activation of the NF-κB and COX-2 expression was observed. In HepG2 cells, conjugates increased ROS production resulting from a reduced antioxidant defense, induced apoptosis, and inhibited cell proliferation. In addition, the OAO morpholide derivative and its DCL hybrid reduced the tumor volume in mice bearing xenografts. In conclusion, our study demonstrated that conjugating diclofenac with the OAO morpholide and a benzyl ester might enhance its anti-cancer activity in HCC. Full article

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19 pages, 2275 KiB

Open AccessReview

Repurposing Drugs to Treat Heart and Brain Illness

by Maranda S. Cantrell, Alejandro Soto-Avellaneda, Jackson D. Wall, Aaron D. Ajeti, Brad E. Morrison, Lisa R. Warner and Owen M. McDougal

Pharmaceuticals 2021, 14(6), 573; https://doi.org/10.3390/ph14060573 - 16 Jun 2021

Cited by 4 | Viewed by 5381

Abstract

Drug development is a complicated, slow and expensive process with high failure rates. One strategy to mitigate these factors is to recycle existing drugs with viable safety profiles and have gained Food and Drug Administration approval following extensive clinical trials. Cardiovascular and neurodegenerative [...] Read more.

Drug development is a complicated, slow and expensive process with high failure rates. One strategy to mitigate these factors is to recycle existing drugs with viable safety profiles and have gained Food and Drug Administration approval following extensive clinical trials. Cardiovascular and neurodegenerative diseases are difficult to treat, and there exist few effective therapeutics, necessitating the development of new, more efficacious drugs. Recent scientific studies have led to a mechanistic understanding of heart and brain disease progression, which has led researchers to assess myriad drugs for their potential as pharmacological treatments for these ailments. The focus of this review is to survey strategies for the selection of drug repurposing candidates and provide representative case studies where drug repurposing strategies were used to discover therapeutics for cardiovascular and neurodegenerative diseases, with a focus on anti-inflammatory processes where new drug alternatives are needed. Full article

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17 pages, 7447 KiB

Open AccessArticle

Potential Tamoxifen Repurposing to Combat Infections by Multidrug-Resistant Gram-Negative Bacilli

by Andrea Miró-Canturri, Rafael Ayerbe-Algaba, Raquel del Toro, Manuel Enrique-Jiménez Mejías, Jerónimo Pachón and Younes Smani

Pharmaceuticals 2021, 14(6), 507; https://doi.org/10.3390/ph14060507 - 26 May 2021

Cited by 6 | Viewed by 3625

Abstract

The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) [...] Read more.

The development of new strategic therapies for multidrug-resistant bacteria, like the use of non-antimicrobial approaches and/or drugs repurposed to be used as monotherapies or in combination with clinically relevant antibiotics, has become urgent. A therapeutic alternative for infections by multidrug-resistant Gram-negative bacilli (MDR-GNB) is immune system modulation to improve the infection clearance. We showed that immunocompetent mice pretreated with tamoxifen at 80 mg/kg/d for three days and infected with Acinetobacter baumannii, Pseudomonas aeruginosa, or Escherichia coli in peritoneal sepsis models showed reduced release of the monocyte chemotactic protein-1 (MCP-1) and its signaling pathway interleukin-18 (IL-18), and phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). This reduction of MCP-1 induced the reduction of migration of inflammatory monocytes and neutrophils from the bone marrow to the blood. Indeed, pretreatment with tamoxifen in murine peritoneal sepsis models reduced the bacterial load in tissues and blood, and increased mice survival from 0% to 60–100%. Together, these data show that tamoxifen presents therapeutic efficacy against MDR A. baumannii, P. aeruginosa, and E. coli in experimental models of infection and may be a new candidate to be repurposed as a treatment for GNB infections. Full article

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45 pages, 2549 KiB

Open AccessReview

Chemical Classes Presenting Novel Antituberculosis Agents Currently in Different Phases of Drug Development: A 2010–2020 Review

by Klaudia T. Angula, Lesetja J. Legoabe and Richard M. Beteck

Pharmaceuticals 2021, 14(5), 461; https://doi.org/10.3390/ph14050461 - 13 May 2021

Cited by 32 | Viewed by 6108

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration [...] Read more.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern; herein, we have compiled drug-drug interaction reports, as well as efficacy reports for drug combinations studies involving antitubercular agents in clinical development. Full article

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16 pages, 9006 KiB

Open AccessArticle

Screening of Benzimidazole-Based Anthelmintics and Their Enantiomers as Repurposed Drug Candidates in Cancer Therapy

by Rosalba Florio, Simone Carradori, Serena Veschi, Davide Brocco, Teresa Di Genni, Roberto Cirilli, Adriano Casulli, Alessandro Cama and Laura De Lellis

Pharmaceuticals 2021, 14(4), 372; https://doi.org/10.3390/ph14040372 - 17 Apr 2021

Cited by 27 | Viewed by 5886

Abstract

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 [...] Read more.

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. Full article

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35 pages, 1113 KiB

Open AccessReview

Drug Repurposing Opportunities in Pancreatic Ductal Adenocarcinoma

by Rita Rebelo, Bárbara Polónia, Lúcio Lara Santos, M. Helena Vasconcelos and Cristina P. R. Xavier

Pharmaceuticals 2021, 14(3), 280; https://doi.org/10.3390/ph14030280 - 20 Mar 2021

Cited by 15 | Viewed by 5832

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the deadliest tumors worldwide. The diagnosis is often possible only in the latter stages of the disease, with patients already presenting an advanced or metastatic tumor. It is also one of the cancers with poorest prognosis, presenting a five-year survival rate of around 5%. Treatment of PDAC is still a major challenge, with cytotoxic chemotherapy remaining the basis of systemic therapy. However, no major advances have been made recently, and therapeutic options are limited and highly toxic. Thus, novel therapeutic options are urgently needed. Drug repurposing is a strategy for the development of novel treatments using approved or investigational drugs outside the scope of the original clinical indication. Since repurposed drugs have already completed several stages of the drug development process, a broad range of data is already available. Thus, when compared with de novo drug development, drug repurposing is time-efficient, inexpensive and has less risk of failure in future clinical trials. Several repurposing candidates have been investigated in the past years for the treatment of PDAC, as single agents or in combination with conventional chemotherapy. This review gives an overview of the main drugs that have been investigated as repurposing candidates, for the potential treatment of PDAC, in preclinical studies and clinical trials. Full article

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15 pages, 3349 KiB

Open AccessCommunication

Old Drug, New Trick: Tilorone, a Broad-Spectrum Antiviral Drug as a Potential Anti-Fibrotic Therapeutic for the Diseased Heart

by Duncan Horlock, David M. Kaye, Catherine E. Winbanks, Xiao-Ming Gao, Helen Kiriazis, Daniel G. Donner, Paul Gregorevic, Julie R. McMullen and Bianca C. Bernardo

Pharmaceuticals 2021, 14(3), 263; https://doi.org/10.3390/ph14030263 - 15 Mar 2021

Cited by 4 | Viewed by 3920

Abstract

Cardiac fibrosis is associated with most forms of cardiovascular disease. No reliable therapies targeting cardiac fibrosis are available, thus identifying novel drugs that can resolve or prevent fibrosis is needed. Tilorone, an antiviral agent, can prevent fibrosis in a mouse model of lung [...] Read more.

Cardiac fibrosis is associated with most forms of cardiovascular disease. No reliable therapies targeting cardiac fibrosis are available, thus identifying novel drugs that can resolve or prevent fibrosis is needed. Tilorone, an antiviral agent, can prevent fibrosis in a mouse model of lung disease. We investigated the anti-fibrotic effects of tilorone in human cardiac fibroblasts in vitro by performing a radioisotopic assay for [³H]-proline incorporation as a proxy for collagen synthesis. Exploratory studies in human cardiac fibroblasts treated with tilorone (10 µM) showed a significant reduction in transforming growth factor-β induced collagen synthesis compared to untreated fibroblasts. To determine if this finding could be recapitulated in vivo, mice with established pathological remodelling due to four weeks of transverse aortic constriction (TAC) were administered tilorone (50 mg/kg, i.p) or saline every third day for eight weeks. Treatment with tilorone was associated with attenuation of fibrosis (assessed by Masson’s trichrome stain), a favourable cardiac gene expression profile and no further deterioration of cardiac systolic function determined by echocardiography compared to saline treated TAC mice. These data demonstrate that tilorone has anti-fibrotic actions in human cardiac fibroblasts and the adult mouse heart, and represents a potential novel therapy to treat fibrosis associated with heart failure. Full article

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29 pages, 7275 KiB

Open AccessArticle

Tioconazole and Chloroquine Act Synergistically to Combat Doxorubicin-Induced Toxicity via Inactivation of PI3K/AKT/mTOR Signaling Mediated ROS-Dependent Apoptosis and Autophagic Flux Inhibition in MCF-7 Breast Cancer Cells

by Afnan H. El-Gowily, Samah A. Loutfy, Ehab M. M. Ali, Tarek M. Mohamed and Mohammed A. Mansour

Pharmaceuticals 2021, 14(3), 254; https://doi.org/10.3390/ph14030254 - 11 Mar 2021

Cited by 18 | Viewed by 5463

Abstract

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling [...] Read more.

Cancer is a complex devastating disease with enormous treatment challenges, including chemo- and radiotherapeutic resistance. Combination therapy demonstrated a promising strategy to target hard-to-treat cancers and sensitize cancer cells to conventional anti-cancer drugs such as doxorubicin. This study aimed to establish molecular profiling and therapeutic efficacy assessment of chloroquine and/or tioconazole (TIC) combination with doxorubicin (DOX) as anew combination model in MCF-7 breast cancer. The drugs are tested against apoptotic/autophagic pathways and related redox status. Molecular docking revealed that chloroquine (CQ) and TIC could be potential PI3K and ATG4B pathway inhibitors. Combination therapy significantly inhibited cancer cell viability, PI3K/AkT/mTOR pathway, and tumor-supporting autophagic flux, however, induced apoptotic pathways and altered nuclear genotoxic feature. Our data revealed that the combination cocktail therapy markedly inhibited tumor proliferation marker (KI-67) and cell growth, along with the accumulation of autophagosomes and elevation of LC3-II and p62 levels indicated autophagic flux blockage and increased apoptosis. Additionally, CQ and/or TIC combination therapy with DOX exerts its activity on the redox balance of cancer cells mediated ROS-dependent apoptosis induction achieved by GPX3 suppression. Besides, Autophagy inhibition causes moderately upregulation in ATGs 5,7 redundant proteins strengthened combinations induced apoptosis, whereas inhibition of PI3K/AKT/mTOR pathway with Beclin-1 upregulation leading to cytodestructive autophagy with overcome drug resistance effectively in curing cancer. Notably, the tumor growth inhibition and various antioxidant effects were observed in vivo. These results suggest CQ and/or TIC combination with DOX could act as effective cocktail therapy targeting autophagy and PI3K/AKT/mTOR pathways in MCF-7 breast cancer cells and hence, sensitizes cancer cells to doxorubicin treatment and combat its toxicity. Full article

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2020

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13 pages, 1227 KiB

Open AccessArticle

Tree-Based QSAR Model for Drug Repurposing in the Discovery of New Antibacterial Compounds against Escherichia coli

by Beatriz Suay-Garcia, Antonio Falcó, J. Ignacio Bueso-Bordils, Gerardo M. Anton-Fos, M. Teresa Pérez-Gracia and Pedro A. Alemán-López

Pharmaceuticals 2020, 13(12), 431; https://doi.org/10.3390/ph13120431 - 28 Nov 2020

Cited by 11 | Viewed by 2999

Abstract

Drug repurposing appears as an increasing popular tool in the search of new treatment options against bacteria. In this paper, a tree-based classification method using Linear Discriminant Analysis (LDA) and discrete indexes was used to create a QSAR (Quantitative Structure-Activity Relationship) model to [...] Read more.

Drug repurposing appears as an increasing popular tool in the search of new treatment options against bacteria. In this paper, a tree-based classification method using Linear Discriminant Analysis (LDA) and discrete indexes was used to create a QSAR (Quantitative Structure-Activity Relationship) model to predict antibacterial activity against Escherichia coli. The model consists on a hierarchical decision tree in which a discrete index is used to divide compounds into groups according to their values for said index in order to construct probability spaces. The second step consists in the calculation of a discriminant function which determines the prediction of the model. The model was used to screen the DrugBank database, identifying 134 drugs as possible antibacterial candidates. Out of these 134 drugs, 8 were antibacterial drugs, 67 were drugs approved for different pathologies and 55 were drugs in experimental stages. This methodology has proven to be a viable alternative to the traditional methods used to obtain prediction models based on LDA and its application provides interesting new drug candidates to be studied as repurposed antibacterial treatments. Furthermore, the topological indexes Nclass and Numhba have proven to have the ability to group active compounds effectively, which suggests a close relationship between them and the antibacterial activity of compounds against E. coli. Full article

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16 pages, 1587 KiB

Open AccessPerspective

A Multi-Objective Approach for Anti-Osteosarcoma Cancer Agents Discovery through Drug Repurposing

by Alejandro Cabrera-Andrade, Andrés López-Cortés, Gabriela Jaramillo-Koupermann, Humberto González-Díaz, Alejandro Pazos, Cristian R. Munteanu, Yunierkis Pérez-Castillo and Eduardo Tejera

Pharmaceuticals 2020, 13(11), 409; https://doi.org/10.3390/ph13110409 - 22 Nov 2020

Cited by 9 | Viewed by 5077

Abstract

Osteosarcoma is the most common type of primary malignant bone tumor. Although nowadays 5-year survival rates can reach up to 60–70%, acute complications and late effects of osteosarcoma therapy are two of the limiting factors in treatments. We developed a multi-objective algorithm for [...] Read more.

Osteosarcoma is the most common type of primary malignant bone tumor. Although nowadays 5-year survival rates can reach up to 60–70%, acute complications and late effects of osteosarcoma therapy are two of the limiting factors in treatments. We developed a multi-objective algorithm for the repurposing of new anti-osteosarcoma drugs, based on the modeling of molecules with described activity for HOS, MG63, SAOS2, and U2OS cell lines in the ChEMBL database. Several predictive models were obtained for each cell line and those with accuracy greater than 0.8 were integrated into a desirability function for the final multi-objective model. An exhaustive exploration of model combinations was carried out to obtain the best multi-objective model in virtual screening. For the top 1% of the screened list, the final model showed a BEDROC = 0.562, EF = 27.6, and AUC = 0.653. The repositioning was performed on 2218 molecules described in DrugBank. Within the top-ranked drugs, we found: temsirolimus, paclitaxel, sirolimus, everolimus, and cabazitaxel, which are antineoplastic drugs described in clinical trials for cancer in general. Interestingly, we found several broad-spectrum antibiotics and antiretroviral agents. This powerful model predicts several drugs that should be studied in depth to find new chemotherapy regimens and to propose new strategies for osteosarcoma treatment. Full article

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17 pages, 1306 KiB

Open AccessReview

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs

by Simona Federica Spampinato, Grazia Ilaria Caruso, Rocco De Pasquale, Maria Angela Sortino and Sara Merlo

Pharmaceuticals 2020, 13(4), 60; https://doi.org/10.3390/ph13040060 - 1 Apr 2020

Cited by 239 | Viewed by 21426

Abstract

Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and [...] Read more.

Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary. We here analyzed current treatments for wound healing, but mainly focused the attention on few classes of drugs that are already in the market with different indications, but that have shown in preclinical and few clinical trials the potentiality to be used in the treatment of impaired wound healing. In particular, repurposing of the antiglycemic agents dipeptidylpeptidase 4 (DPP4) inhibitors and metformin, but also, statins and phenyotin have been analyzed. All show encouraging results in the treatment of chronic wounds, but additional, well designed studies are needed to allow these drugs access to the clinics in the therapy of impaired wound healing. Full article

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16 pages, 5532 KiB

Open AccessArticle

In Vitro Anti-Prostate Cancer Activity of Two Ebselen Analogues

by Katarzyna B. Kaczor-Keller, Anna Pawlik, Jacek Scianowski, Agata Pacuła, Magdalena Obieziurska, Fabio Marcheggiani, Ilenia Cirilli, Luca Tiano and Jedrzej Antosiewicz

Pharmaceuticals 2020, 13(3), 47; https://doi.org/10.3390/ph13030047 - 17 Mar 2020

Cited by 12 | Viewed by 4169

Abstract

Scientific research has been underway for decades in order to develop an effective anticancer drug, and it has become crucial to find a novel and effective chemotherapeutics in the case of prostate cancer treatment. Ebselen derivatives have been shown to possess a variety [...] Read more.

Scientific research has been underway for decades in order to develop an effective anticancer drug, and it has become crucial to find a novel and effective chemotherapeutics in the case of prostate cancer treatment. Ebselen derivatives have been shown to possess a variety of biological activities, including cytostatic and cytotoxic action against tumor cells. In this study, the cytotoxic effect and anticancer mechanism of action of two organoselenium compounds— (N-allyl-1,2-benzisoselenazol-3(2H)-one (N-allyl-BS) and N-(3-methylbutyl)-1,2-benzisoselenazol-3(2H)-one) (N-(3-mb)-BS)—were investigated on two phenotypically different prostate cancer cell lines DU 145 and PC-3. The influence of analyzed compounds on the viability parameter was also assessed on normal prostate cell line PNT1A. The results showed that both organoselenium compounds (OSCs) efficiently inhibited cancer cell proliferation, whereas normal PNT1A cells were less sensitive to the analazyed ebselen analouges. Both OSCs induced G2/M cell cycle arrest and prompted cell death through apoptosis. The detection of cleaved Poly (ADP-ribose) Polymerase (PARP) confirmed this. In addition, N-allyl-BS and N-(3-m)-b-BS increased the level of reactive oxygen species (ROS) formation, however only N-allyl-BS induced DNA damage. Based on our data, we assume that OSCs’ anticancer action can be associated with oxidative stress induction and inactivation of the Akt- dependent signalling pathway. In conclusion, our data demonstrate that ebselen derivatives showed strong cytotoxic efficiency towards prostate cancer cells and may be elucidated as a novel, potent anticancer agent. Full article

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2019

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31 pages, 1206 KiB

Open AccessReview

Sugar-Lowering Drugs for Type 2 Diabetes Mellitus and Metabolic Syndrome—Review of Classical and New Compounds: Part-I

by Raquel Vieira, Selma B. Souto, Elena Sánchez-López, Ana López Machado, Patricia Severino, Sajan Jose, Antonello Santini, Ana Fortuna, Maria Luisa García, Amelia M. Silva and Eliana B. Souto

Pharmaceuticals 2019, 12(4), 152; https://doi.org/10.3390/ph12040152 - 10 Oct 2019

Cited by 110 | Viewed by 12526

Abstract

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia together with disturbances in the metabolism of carbohydrates, proteins and fat, which in general results from an insulin availability and need imbalance. In a great number of patients, marketed anti-glycemic agents have [...] Read more.

Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia together with disturbances in the metabolism of carbohydrates, proteins and fat, which in general results from an insulin availability and need imbalance. In a great number of patients, marketed anti-glycemic agents have shown poor effectiveness in maintaining a long-term glycemic control, thus being associated with severe adverse effects and leading to an emerging interest in natural compounds (e.g., essential oils and other secondary plant metabolites, namely, flavonoid-rich compounds) as a novel approach for prevention, management and/or treatment of either non-insulin-dependent diabetes mellitus (T2DM, type 2 DM) and/or Metabolic Syndrome (MS). In this review, some of these promising glucose-lowering agents will be comprehensively discussed. Full article

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12 pages, 778 KiB

Open AccessConcept Paper

Methylxanthines: Potential Therapeutic Agents for Glioblastoma

by Daniel Pérez-Pérez, Iannel Reyes-Vidal, Elda Georgina Chávez-Cortez, Julio Sotelo and Roxana Magaña-Maldonado

Pharmaceuticals 2019, 12(3), 130; https://doi.org/10.3390/ph12030130 - 7 Sep 2019

Cited by 10 | Viewed by 5455

Abstract

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of [...] Read more.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of neoplastic cells. One of these pathways is the deregulation of phosphodiesterases (PDEs). These enzymes participate in the development of GBM and may have value as therapeutic targets to treat GBM. Methylxanthines (MXTs) such as caffeine, theophylline, and theobromine are PDE inhibitors and constitute a promising therapeutic anti-cancer agent against GBM. MTXs also regulate various cell processes such as proliferation, migration, cell death, and differentiation; these processes are related to cancer progression, making MXTs potential therapeutic agents in GBM. Full article

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2018

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18 pages, 590 KiB

Open AccessArticle

Proximal Pathway Enrichment Analysis for Targeting Comorbid Diseases via Network Endopharmacology

by Joaquim Aguirre-Plans, Janet Piñero, Jörg Menche, Ferran Sanz, Laura I. Furlong, Harald H. H. W. Schmidt, Baldo Oliva and Emre Guney

Pharmaceuticals 2018, 11(3), 61; https://doi.org/10.3390/ph11030061 - 22 Jun 2018

Cited by 34 | Viewed by 10172

Abstract

The past decades have witnessed a paradigm shift from the traditional drug discovery shaped around the idea of “one target, one disease” to polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a [...] Read more.

The past decades have witnessed a paradigm shift from the traditional drug discovery shaped around the idea of “one target, one disease” to polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmacology paradigm is to target common biological pathways involved in diseases via endopharmacology (multiple targets, multiple diseases). In this study, we present proximal pathway enrichment analysis (PxEA) for pinpointing drugs that target common disease pathways towards network endopharmacology. PxEA uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs by their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. Using PxEA, we show that many drugs indicated for autoimmune disorders are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer’s disease, two conditions that have recently gained attention due to the increased comorbidity among patients. Full article

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Graphical abstract

21 pages, 288 KiB

Open AccessReview

Changing Trends in Computational Drug Repositioning

by Jaswanth K. Yella, Suryanarayana Yaddanapudi, Yunguan Wang and Anil G. Jegga

Pharmaceuticals 2018, 11(2), 57; https://doi.org/10.3390/ph11020057 - 5 Jun 2018

Cited by 131 | Viewed by 12876

Abstract

Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated—“The most fruitful basis for the discovery of a new drug is to start with an old [...] Read more.

Efforts to maximize the indications potential and revenue from drugs that are already marketed are largely motivated by what Sir James Black, a Nobel Prize-winning pharmacologist advocated—“The most fruitful basis for the discovery of a new drug is to start with an old drug”. However, rational design of drug mixtures poses formidable challenges because of the lack of or limited information about in vivo cell regulation, mechanisms of genetic pathway activation, and in vivo pathway interactions. Hence, most of the successfully repositioned drugs are the result of “serendipity”, discovered during late phase clinical studies of unexpected but beneficial findings. The connections between drug candidates and their potential adverse drug reactions or new applications are often difficult to foresee because the underlying mechanism associating them is largely unknown, complex, or dispersed and buried in silos of information. Discovery of such multi-domain pharmacomodules—pharmacologically relevant sub-networks of biomolecules and/or pathways—from collection of databases by independent/simultaneous mining of multiple datasets is an active area of research. Here, while presenting some of the promising bioinformatics approaches and pipelines, we summarize and discuss the current and evolving landscape of computational drug repositioning. Full article

21 pages, 3114 KiB

Open AccessReview

Old Drugs as New Treatments for Neurodegenerative Diseases

by Fernando Durães, Madalena Pinto and Emília Sousa

Pharmaceuticals 2018, 11(2), 44; https://doi.org/10.3390/ph11020044 - 11 May 2018

Cited by 247 | Viewed by 23388

Abstract

Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments [...] Read more.

Neurodegenerative diseases are increasing in number, given that the general global population is becoming older. They manifest themselves through mechanisms that are not fully understood, in many cases, and impair memory, cognition and movement. Currently, no neurodegenerative disease is curable, and the treatments available only manage the symptoms or halt the progression of the disease. Therefore, there is an urgent need for new treatments for this kind of disease, since the World Health Organization has predicted that neurodegenerative diseases affecting motor function will become the second-most prevalent cause of death in the next 20 years. New therapies can come from three main sources: synthesis, natural products, and existing drugs. This last source is known as drug repurposing, which is the most advantageous, since the drug’s pharmacokinetic and pharmacodynamic profiles are already established, and the investment put into this strategy is not as significant as for the classic development of new drugs. There have been several studies on the potential of old drugs for the most relevant neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, Multiple Sclerosis and Amyotrophic Lateral Sclerosis. Full article

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20 pages, 4152 KiB

Open AccessArticle

Mitoxantrone is More Toxic than Doxorubicin in SH-SY5Y Human Cells: A ‘Chemobrain’ In Vitro Study

by Daniela Almeida, Rita Pinho, Verónica Correia, Jorge Soares, Maria De Lourdes Bastos, Félix Carvalho, João Paulo Capela and Vera Marisa Costa

Pharmaceuticals 2018, 11(2), 41; https://doi.org/10.3390/ph11020041 - 5 May 2018

Cited by 16 | Viewed by 6433

Abstract

The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro [...] Read more.

The potential neurotoxic effects of anticancer drugs, like doxorubicin (DOX) and mitoxantrone (MTX; also used in multiple sclerosis), are presently important reasons for concern, following epidemiological data indicating that cancer survivors submitted to chemotherapy may suffer cognitive deficits. We evaluated the in vitro neurotoxicity of two commonly used chemotherapeutic drugs, DOX and MTX, and study their underlying mechanisms in the SH-SY5Y human neuronal cell model. Undifferentiated human SH-SY5Y cells were exposed to DOX or MTX (0.13, 0.2 and 0.5 μM) for 48 h and two cytotoxicity assays were performed, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) reduction and the neutral red (NR) incorporation assays. Phase contrast microphotographs, Hoechst, and acridine orange/ethidium bromide stains were performed. Mitochondrial membrane potential was also assessed. Moreover, putative protective drugs, namely the antioxidants N-acetyl-l-cysteine (NAC; 1 mM) and 100 μM tiron, the inhibitor of caspase-3/7, Ac-DEVD-CHO (100 μM), and a protein synthesis inhibitor, cycloheximide (CHX; 10 nM), were tested to prevent DOX- or MTX-induced toxicity. The MTT reduction assay was also done in differentiated SH-SY5Y cells following exposure to 0.2 μM DOX or MTX. MTX was more toxic than DOX in both cytotoxicity assays and according to the morphological analyses. MTX also evoked a higher number of apoptotic nuclei than DOX. Both drugs, at the 0.13 μM concentration, caused mitochondrial membrane potential depolarization after a 48-h exposure. Regarding the putative neuroprotectors, 1 mM NAC was not able to prevent the cytotoxicity caused by either drug. Notwithstanding, 100 μM tiron was capable of partially reverting MTX-induced cytotoxicity in the NR uptake assay. One hundred μM Ac-DEVD-CHO and 10 nM cycloheximide (CHX) also partially prevented the toxicity induced by DOX in the NR uptake assay. MTX was more toxic than DOX in differentiated SH-SY5Y cells, while MTX had similar toxicity in differentiated and undifferentiated SH-SY5Y cells. In fact, MTX was the most neurotoxic drug tested and the mechanisms involved seem dissimilar among drugs. Thus, its toxicity mechanisms need to be further investigated as to determine the putative neurotoxicity for multiple sclerosis and cancer patients. Full article

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15 pages, 9398 KiB

Open AccessArticle

A Novel Interaction Between the TLR7 and a Colchicine Derivative Revealed Through a Computational and Experimental Study

by Francesco Gentile, Marco A. Deriu, Khaled Barakat, Andrea Danani and Jack Tuszynski

Pharmaceuticals 2018, 11(1), 22; https://doi.org/10.3390/ph11010022 - 16 Feb 2018

Cited by 3 | Viewed by 5186

Abstract

The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of [...] Read more.

The Toll-Like Receptor 7 (TLR7) is an endosomal membrane receptor involved in the innate immune system response. Its best-known small molecule activators are imidazoquinoline derivatives such as imiquimod (R-837) and resiquimod (R-848). Recently, an interaction between R-837 and the colchicine binding site of tubulin was reported. To investigate the possibility of an interaction between structural analogues of colchicine and the TLR7, a recent computational model for the dimeric form of the TLR7 receptor was used to determine a possible interaction with a colchicine derivative called CR42-24, active as a tubulin polymerization inhibitor. The estimated values of the binding energy of this molecule with respect to the TLR7 receptor were comparable to the energies of known binders as reported in a previous study. The binding to the TLR7 was further assessed by introducing genetic transformations in the TLR7 gene in cancer cell lines and exposing them to the compound. A negative shift of the IC50 value in terms of cell growth was observed in cell lines carrying the mutated TLR7 gene. The reported study suggests a possible interaction between TLR7 and a colchicine derivative, which can be explored for rational design of new drugs acting on this receptor by using a colchicine scaffold for additional modifications. Full article

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34 pages, 4659 KiB

Open AccessReview

Drug Repurposing for Schistosomiasis: Combinations of Drugs or Biomolecules

by Maria João Gouveia, Paul J. Brindley, Fátima Gärtner, José M. Correia da Costa and Nuno Vale

Pharmaceuticals 2018, 11(1), 15; https://doi.org/10.3390/ph11010015 - 5 Feb 2018

Cited by 52 | Viewed by 9517

Abstract

Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated [...] Read more.

Schistosomiasis is a major neglected tropical disease. Control of schistosomiasis currently relies on a single drug, praziquantel, and despite its efficacy against the all schistosome species that parasitize humans, it displays some problematic drawbacks and alone is ineffective in counteracting adverse pathologies associated with infection. Moreover, due to the development of the potential emergence of PZQ-resistant strains, the search for additional or alternative antischistosomal drugs have become a public health priority. The current drug discovery for schistosomiasis has been slow and uninspiring. By contrast, repurposing of existing approved drugs may offer a safe, rapid and cost-effective alternative. Combined treatment with PZQ and other drugs with different mode of action, i.e., antimalarials, shows promise results. In addition, a combination of anthelminthic drugs with antioxidant might be advantageous for modulating oxidative processes associated with schistosomiasis. Herein, we review studies dealing with combination therapies that involve PZQ and other anthelminthic drugs and/or antioxidant agents in treatment of schistosomiasis. Whereas PZQ combined with antioxidant agents might or might not interfere with anthelminthic efficacy, combinations may nonetheless ameliorate tissue damage and infection-associated complications. In fact, alone or combine with other drugs, antioxidants might be a valuable adjuvant to reduce morbidity and mortality of schistosomiasis. Therefore, attempting new combinations of anthelmintic drugs with other biomolecules such as antioxidants provides new avenues for discovery of alternatives to PZQ. Full article

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2017

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3537 KiB

Open AccessArticle

A Triphenylphosphonium-Functionalized Mitochondriotropic Nanocarrier for Efficient Co-Delivery of Doxorubicin and Chloroquine and Enhanced Antineoplastic Activity

by Katerina N. Panagiotaki, Zili Sideratou, Spiros A. Vlahopoulos, Maria Paravatou-Petsotas, Michael Zachariadis, Nikolas Khoury, Vassilis Zoumpourlis and Dimitris Tsiourvas

Pharmaceuticals 2017, 10(4), 91; https://doi.org/10.3390/ph10040091 - 21 Nov 2017

Cited by 22 | Viewed by 6672

Abstract

Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the [...] Read more.

Drug delivery systems that target subcellular organelles and, in particular, mitochondria are considered to have great potential in treating disorders that are associated with mitochondrial dysfunction, including cancer or neurodegenerative diseases. To this end, a novel hyperbranched mitochondriotropic nanocarrier was developed for the efficient co-delivery of two different (both in chemical and pharmacological terms) bioactive compounds. The carrier is based on hyperbranched poly(ethyleneimine) functionalized with triphenylphosphonium groups that forms ~100 nm diameter nanoparticles in aqueous media and can encapsulate doxorubicin (DOX), a well-known anti-cancer drug, and chloroquine (CQ), a known chemosensitizer with arising potential in anticancer medication. The anticancer activity of this system against two aggressive DOX-resistant human prostate adenocarcinoma cell lines and in in vivo animal studies was assessed. The co-administration of encapsulated DOX and CQ leads to improved cell proliferation inhibition at extremely low DOX concentrations (0.25 μΜ). In vivo experiments against DU145 human prostate cancer cells grafted on immunodeficient mice resulted in tumor growth arrest during the three-week administration period and no pervasive side effects. The findings put forward the potential of such targeted low dose combination treatments as a therapeutic scheme with minimal adverse effects. Full article

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