-
The Journal of Dermatology Feb 2022Cutaneous lymphoma is generally treated with skin-directed therapies (SDT) during the early and localized stages. For the refractory or advanced stages, systemic... (Review)
Review
Cutaneous lymphoma is generally treated with skin-directed therapies (SDT) during the early and localized stages. For the refractory or advanced stages, systemic therapies are used. Previously, retinoids and interferons were used for SDT-resistant cases. Only a few chemotherapy options were available for more advanced disease. In recent years, many novel agents have been introduced and the strategy for systemic therapy has changed, especially for cutaneous T-cell lymphoma (CTCL). For SDT, helical tomotherapy, a new radiation modality, has been drawing attention as an option for radiotherapy. Targeted therapies such as histone deacetylase inhibitors, mogamulizumab, brentuximab vedotin, and denileukin diftitox are new treatment options. Chemotherapy agents such as gemcitabine and pralatrexate have been introduced; they are expected to have meaningful efficacy as monotherapy. Allogeneic hematopoietic stem cell transplantation is still considered for young patients with advanced CTCL as the only potentially curative treatment.
Topics: Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Cutaneous; Retinoids; Skin Neoplasms
PubMed: 34958516
DOI: 10.1111/1346-8138.16289 -
Hepatology Communications Jun 2022During the pandemic, dexamethasone (DEX), remdesivir (RDV), hydroxychloroquine (HCQ), thapsigargin (TG), camostat mesylate (CaM), and pralatrexate were repurposed drugs...
During the pandemic, dexamethasone (DEX), remdesivir (RDV), hydroxychloroquine (HCQ), thapsigargin (TG), camostat mesylate (CaM), and pralatrexate were repurposed drugs for coronavirus disease 2019 (COVID-19). However, the side effects on the liver associated with the anti-COVID therapies are unknown. Cellular stresses by these drugs at 0-30 μM were studied using HepG2, Huh7, and/or primary human hepatocytes. DEX or RDV induced endoplasmic reticulum stress with increased X-box binding protein 1 and autophagic response with increased accumulation of microtubule-associated protein 1A/1B-light chain 3 (LC3-II). DEX and RDV had additive effects on the stress responses in the liver cells, which further increased expression of activating transcription factor 4 and C/EBP homology protein 1 (CHOP), and cell death. Alcohol pretreatment (50 mM) and DEX induced greater cellular stress responses than DEX and RDV. Pralatrexate induced Golgi fragmentation, cell cycle arrest at G0/G1 phase, activations of poly (ADP-ribose) polymerase-1 (PARP) and caspases, and cell death. Pralatrexate and alcohol had synergistic effects on the cell death mediators of Bim, caspase3, and PARP. The protease inhibitor CaM and TG induced autophagic response and mitochondrial stress with altered mitochondrial membrane potential, B-cell lymphoma 2, and cytochrome C. TG and HCQ induced autophagic response markers of Unc-51 like autophagy activating kinase, LC3-II, Beclin1, and Atg5, and severe ER stress marker CHOP. Conclusion: These results suggest that the anti-COVID-19 drugs, especially with drug-drug or alcohol-drug combinations, cause cellular stress responses and injuries in the liver cells.
Topics: Endoplasmic Reticulum Stress; Ethanol; Hepatocytes; Humans; Microtubule-Associated Proteins; Poly(ADP-ribose) Polymerase Inhibitors; Thapsigargin; Transcription Factor CHOP; COVID-19 Drug Treatment
PubMed: 34910385
DOI: 10.1002/hep4.1887 -
Journal of Applied Microbiology Mar 2022Antimicrobial resistance (AMR) has become a global concern. Developing novel antimicrobials is one of the most effective approaches in tackling AMR. Considering its...
AIM
Antimicrobial resistance (AMR) has become a global concern. Developing novel antimicrobials is one of the most effective approaches in tackling AMR. Considering its relatively low cost and risk, drug repurposing has been proposed as a valuable approach for novel antimicrobial discovery. The aim of this study was to screen for antimicrobial compounds against Streptococcus suis, an important zoonotic bacterial pathogen, from an Food and Drug Administration (FDA)-approved drug library.
METHODS AND RESULTS
In this study, we tested the antimicrobial activity of 1815 FDA-approved drugs against S. suis. Sixty-seven hits were obtained that showed a growth inhibition of more than 98%. After excluding already known antibiotics and antiseptics, 12 compounds were subjected to minimal inhibition concentration (MIC) assessment against S. suis. This showed that pralatrexate, daunorubicin (hydrochloride), teniposide, aclacinomycin A hydrochloride and floxuridine gave a relatively low MIC, ranging from 0.85 to 5.25 μg/ml. Apart from pralatrexate, the remaining four drugs could also inhibit the growth of antimicrobial-resistant S. suis. It was also demonstrated that these four drugs had better efficacy against Gram-positive bacteria than Gram-negative bacteria. Cytotoxicity assays showed that floxuridine and teniposide had a relatively high 50% cytotoxic concentration (CC ). The in vivo efficacy of floxuridine was analysed using a Galleria mellonella larvae infection model, and the results showed that floxuridine was effective in treating S. suis infection in vivo.
CONCLUSIONS
Five compounds from the FDA-approved drug library showed high antimicrobial activity against S. suis, among which floxuridine displayed potent in vivo efficacy that is worth further development.
SIGNIFICANCE AND IMPACT OF STUDY
Our study identified several antimicrobial compounds that are effective against S. suis, which provides a valuable starting point for further antimicrobial development.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Humans; Microbial Sensitivity Tests; Pharmaceutical Preparations; Streptococcal Infections; Streptococcus suis; United States; United States Food and Drug Administration
PubMed: 34800069
DOI: 10.1111/jam.15377 -
Frontiers in Microbiology 2021Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the... (Review)
Review
Deep learning significantly accelerates the drug discovery process, and contributes to global efforts to stop the spread of infectious diseases. Besides enhancing the efficiency of screening of antimicrobial compounds against a broad spectrum of pathogens, deep learning has also the potential to efficiently and reliably identify drug candidates against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Consequently, deep learning has been successfully used for the identification of a number of potential drugs against SARS-CoV-2, including Atazanavir, Remdesivir, Kaletra, Enalaprilat, Venetoclax, Posaconazole, Daclatasvir, Ombitasvir, Toremifene, Niclosamide, Dexamethasone, Indomethacin, Pralatrexate, Azithromycin, Palmatine, and Sauchinone. This mini-review discusses recent advances and future perspectives of deep learning-based SARS-CoV-2 drug discovery.
PubMed: 34777286
DOI: 10.3389/fmicb.2021.739684 -
Blood Reviews Mar 2022Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of aggressive non-Hodgkin lymphomas that are far less sensitive to chemotherapy than their B-cell... (Review)
Review
Peripheral T-cell Lymphomas (PTCL) are a heterogenous group of aggressive non-Hodgkin lymphomas that are far less sensitive to chemotherapy than their B-cell counterparts. Despite their poor prognosis, they are treated similarly to most aggressive B-cell lymphomas, heavily relying on CHOP or CHOP-like combination chemotherapy irrespective of their different subtypes or biology. The last decade has seen the emergence of many targeted therapies that include histone deacetylase inhibitors, hypomethylating agents, monoclonal antibodies and PIK3 inhibitors, among others. However, prognosis remains poor especially in the relapsed/refractory setting. Using an extensive pubmed search, the authors will be summarizing the different trials that led to these approved targeted agents as well as novel combination strategies. The fundamental recognition that different subtypes of PTCL have specific biological features that drive not only proliferation, but also responses to different treatment approaches, should be informing the design of future clinical trials.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Lymphoma, T-Cell, Peripheral; Prognosis
PubMed: 34716031
DOI: 10.1016/j.blre.2021.100889 -
Internal Medicine Journal Oct 2022Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes...
Peripheral T-cell lymphomas (PTCL) represent a heterogeneous disease group accounting for 10% of non-Hodgkin lymphomas. PTCL patients have typically poorer outcomes compared with aggressive B-cell lymphomas. However, such outcomes are heavily dependent on subtype. Although anthracycline-based regimens such as cyclophosphamide, doxorubicin, vincristine and prednisone remain the standard first-line treatment for most aggressive PTCL, there are important variations including incorporation of novel agents, use of radiotherapy and judicious consideration of stem cell transplantation. Relapsed or refractory disease represents a significant area of unmet need where chemotherapy intensification has limited efficacy and novel agents such as brentuximab vedotin and pralatrexate provide additional opportunities for attainment of remission and potential stem cell transplant. In the future, pre-therapy prognostic biomarkers including genomic characterisation, may aid in risk stratification and help guide initial patient management to improve survival. There is an urgent need to understand better the pathogenesis of PTCL to facilitate novel drug combinatorial approaches to improve survival. This position statement represents an evidence-based synthesis of the literature for application in Australian and New Zealand practice.
Topics: Humans; Lymphoma, T-Cell, Peripheral; Vincristine; Brentuximab Vedotin; Prednisone; Consensus; Follow-Up Studies; Antineoplastic Combined Chemotherapy Protocols; Australia; Cyclophosphamide; Doxorubicin; Biomarkers
PubMed: 34668281
DOI: 10.1111/imj.15595 -
Journal of B.U.ON. : Official Journal... 2021Pralatrexate is a new generation antifolate treatment agent used for the treatment of relapsed or refractory peripheral T-cell lymphomas. This study aims to determine...
PURPOSE
Pralatrexate is a new generation antifolate treatment agent used for the treatment of relapsed or refractory peripheral T-cell lymphomas. This study aims to determine the general characteristics of the patients receiving pralatrexate therapy in Turkey, contributing to the literature on the effectiveness of pralatrexate therapy in peripheral T-cell lymphomas by determining the response levels of such patients to the therapy. The study also attempts to clinically examine the major side effects observed in patients during treatment with pralatrexate.
METHODS
The study included patients with peripheral T-cell lymphoma followed up in the hematology units of several hospitals in Turkey. Overall, 20 patients aged 18 and over were included in the study.
RESULTS
The median age at the time of diagnosis was 58.5 years. PTCL-NOS (Peripheral T-cell lymphoma, not otherwise specified) subtype was in 40% of patients, making the PTCL-NOS the most common subtype in the study. In general, most patients were diagnosed with disease at an advanced stage. Pralatrexate therapy was given to the patients at a median treatment line of 3.5. Pralatrexate dose reduction was required in only 3 patients (15%). Response to pralatrexate therapy with partial remission (PR) and above was observed in 11 (55%) of the patients.
CONCLUSION
Pralatrexate seemed to be a promising novel treatment in relapsed refractory PTCL patients. However, patients receiving pralatrexate should be followed up carefully for skin reactions, mucosal side effects, thrombocytopenia and neutropenia.
Topics: Aminopterin; Female; Humans; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Turkey
PubMed: 34565016
DOI: No ID Found -
Biochemical and Biophysical Research... Oct 2021Heart diseases are known as the most primary causes of mortality worldwide. Although many therapeutic approaches and medications are proposed for these diseases, the...
Heart diseases are known as the most primary causes of mortality worldwide. Although many therapeutic approaches and medications are proposed for these diseases, the identification of novel therapeutics in fatal heart conditions is promptly demanded. Besides, the interplay between gene expression data and molecular docking provides several novel insights to discover more effective and specific drugs for the treatment of the diseases. This study aimed to discover potent therapeutic drugs in the heart diseases based on the expression profile of heart-specific genes exclusively. Initially, the heart-specific and highly expressed genes were identified by comparing the gene expression profile of different body tissues. Subsequently, the druggable-genes were identified using in silico techniques. The interaction between these druggable genes with more than 1600 FDA approved drugs was then investigated using the molecular docking simulation. By comprehensively analyzing RNA-sequencing data obtained from 949 normal tissue samples, 48 heart-specific genes were identified in both the heart development and function. Notably, of these, 24 heart-specific genes were capable to be considered as druggable genes, among which only MYBPC3, MYLK3, and SCN5A genes entered the molecular docking process due to their functions. Afterward, the pharmacokinetics properties of top 10 ligands with the highest binding affinity for these proteins were studied. Accordingly, methylergonovine, fosaprepitant, pralatrexate, daunorubicin, glecaprevir, digoxin, and venetoclax drugs were competent, in order to interact with the target proteins perfectly. It was shown that these medications can be used as specific drugs for the treatment of heart diseases after fulfilling further experiments in this regard.
Topics: Aminoisobutyric Acids; Aminopterin; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Daunorubicin; Digoxin; Drug Repositioning; Gene Expression; Heart Diseases; Humans; Lactams, Macrocyclic; Leucine; Ligands; Methylergonovine; Molecular Docking Simulation; Morpholines; Proline; Quinoxalines; Sulfonamides
PubMed: 34364293
DOI: 10.1016/j.bbrc.2021.07.076 -
BMC Cancer Jul 2021Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic...
BACKGROUND
Pralatrexate (PDX) is a novel antifolate approved for the treatment of patients with relapsed/refractory peripheral T-cell lymphoma, but some patients exhibit intrinsic resistance or develop acquired resistance. Here, we evaluated the mechanisms underlying acquired resistance to PDX and explored potential therapeutic strategies to overcome PDX resistance.
METHODS
To investigate PDX resistance, we established two PDX-resistant T-lymphoblastic leukemia cell lines (CEM and MOLT4) through continuous exposure to increasing doses of PDX. The resistance mechanisms were evaluated by measuring PDX uptake, apoptosis induction and folate metabolism-related protein expression. We also applied gene expression analysis and methylation profiling to identify the mechanisms of resistance. We then explored rational drug combinations using a spheroid (3D)-culture assay.
RESULTS
Compared with their parental cells, PDX-resistant cells exhibited a 30-fold increase in half-maximal inhibitory concentration values. Induction of apoptosis by PDX was significantly decreased in both PDX-resistant cell lines. Intracellular uptake of [C]-PDX decreased in PDX-resistant CEM cells but not in PDX-resistant MOLT4 cells. There was no significant change in expression of dihydrofolate reductase (DHFR) or folylpolyglutamate synthetase (FPGS). Gene expression array analysis revealed that DNA-methyltransferase 3β (DNMT3B) expression was significantly elevated in both cell lines. Gene set enrichment analysis revealed that adipogenesis and mTORC1 signaling pathways were commonly upregulated in both resistant cell lines. Moreover, CpG island hypermethylation was observed in both PDX resistant cells lines. In the 3D-culture assay, decitabine (DAC) plus PDX showed synergistic effects in PDX-resistant cell lines compared with parental lines.
CONCLUSIONS
The resistance mechanisms of PDX were associated with reduced cellular uptake of PDX and/or overexpression of DNMT3B. Epigenetic alterations were also considered to play a role in the resistance mechanism. The combination of DAC and PDX exhibited synergistic activity, and thus, this approach might improve the clinical efficacy of PDX.
Topics: Aminopterin; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; DNA Methylation; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Folic Acid Antagonists; Gene Expression Profiling; Humans; Tumor Cells, Cultured
PubMed: 34332580
DOI: 10.1186/s12885-021-08607-9 -
The Journal of Clinical Endocrinology... Sep 2021Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF...
BACKGROUND
Despite the use of aggressive multimodality treatment, most anaplastic thyroid carcinoma (ATC) patients die within a year of diagnosis. Although the combination of BRAF and MEK inhibitors has recently been approved for use in BRAF-mutated ATC, they remain effective in a minority of patients who are likely to develop drug resistance. There remains a critical clinical need for effective systemic agents for ATC with a reasonable toxicity profile to allow for rapid translational development.
MATERIAL AND METHODS
Twelve human thyroid cancer cell lines with comprehensive genomic characterization were used in a high-throughput screening (HTS) of 257 compounds to select agents with maximal growth inhibition. Cell proliferation, colony formation, orthotopic thyroid models, and patient-derived xenograft (PDX) models were used to validate the selected agents.
RESULTS
Seventeen compounds were effective, and docetaxel, LBH-589, and pralatrexate were selected for additional in vitro and in vivo analysis as they have been previously approved by the US Food and Drug Administration for other cancers. Significant tumor growth inhibition (TGI) was detected in all tested models treated with LBH-589; pralatrexate demonstrated significant TGI in the orthotopic papillary thyroid carcinoma model and 2 PDX models; and docetaxel demonstrated significant TGI only in the context of mutant TP53.
CONCLUSIONS
HTS identified classes of systemic agents that demonstrate preferential effectiveness against aggressive thyroid cancers, particularly those with mutant TP53. Preclinical validation in both orthotopic and PDX models, which are accurate in vivo models mimicking tumor microenvironment, may support initiation of early-phase clinical trials in non-BRAF mutated or refractory to BRAF/MEK inhibition ATC.
Topics: Animals; Antineoplastic Agents; Carcinogenicity Tests; Cell Line, Tumor; Disease Models, Animal; High-Throughput Screening Assays; Humans; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Tumor Microenvironment
PubMed: 34120183
DOI: 10.1210/clinem/dgab424