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1.
Drug Dev Res ; 83(7): 1505-1518, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2007097

ABSTRACT

Carmofur, 1-hexylcarbamoyl-5-fluorouracil (HCFU) is an antineoplastic drug, which has been in clinics in Japan since 1981 for the treatment of colorectal cancer. Subsequently, it was also introduced in China, Korea, and Finland. Besides colorectal cancer, it has also shown antitumor activity in other cancers such as breast, head and neck, pancreatic, gastrointestinal, and solid brain tumors. A prodrug of 5-fluorouracil (5-FU), carmofur has shown better gastrointestinal stability and superior antiproliferative activity compared to its active counterpart 5-FU. Recently, carmofur has gained attention as an acid ceramidase inhibitor and as a potential lead compound against several noncancerous diseases such as coronavirus disease 2019, Krabbe disease, acute lung injury, Parkinson's disease, dementia, childhood ependymoma etc. Carmofur has also been reported to have antifungal, and antimicrobial properties. Nevertheless, no comprehensive review is available on this drug. Herein, we summarized the chemistry, pharmacokinetics, and pharmacology of carmofur based on the literature published between January 1976 and March 2022 as identified from PubMed and Google Scholar search engines.


Subject(s)
Antineoplastic Agents , Brain Neoplasms , COVID-19 , Colorectal Neoplasms , Humans , Child , Fluorouracil/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Brain Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy
2.
Stem Cell Reports ; 17(9): 1959-1975, 2022 09 13.
Article in English | MEDLINE | ID: covidwho-2000717

ABSTRACT

In vitro tissue models hold great promise for modeling diseases and drug responses. Here, we used emulsion microfluidics to form micro-organospheres (MOSs), which are droplet-encapsulated miniature three-dimensional (3D) tissue models that can be established rapidly from patient tissues or cells. MOSs retain key biological features and responses to chemo-, targeted, and radiation therapies compared with organoids. The small size and large surface-to-volume ratio of MOSs enable various applications including quantitative assessment of nutrient dependence, pathogen-host interaction for anti-viral drug screening, and a rapid potency assay for chimeric antigen receptor (CAR)-T therapy. An automated MOS imaging pipeline combined with machine learning overcomes plating variation, distinguishes tumorspheres from stroma, differentiates cytostatic versus cytotoxic drug effects, and captures resistant clones and heterogeneity in drug response. This pipeline is capable of robust assessments of drug response at individual-tumorsphere resolution and provides a rapid and high-throughput therapeutic profiling platform for precision medicine.


Subject(s)
Antineoplastic Agents , Organoids , Antineoplastic Agents/pharmacology , Drug Evaluation, Preclinical/methods , Humans , Microfluidics , Precision Medicine
3.
J Pharm Biomed Anal ; 220: 114989, 2022 Oct 25.
Article in English | MEDLINE | ID: covidwho-1977554

ABSTRACT

Morinda citrifolia Linn (noni) is an important plant in the Pacific Asian region. The fruit has been used as a food source and has shown therapeutical benefits for health. Recently, it has become a source for bioactive compounds. In this study, we investigated the antimicrobial and anticancer activities of alcoholic extracts of Hainan dry noni fruit with machinery assistance and identified their novel compounds by UPLC-Q-Exactive Obitrap-MS/MS. By IE extractor aided method, the extraction of both NFE (Noni Fruit Ethanol) and NFM (Noni Fruit Methanol) solvent crude sample extracts were obtained with recovery yields of 98.48% and 71.65%, respectively. The antimicrobial effect of the crude extracts was subjected to disc diffusion test screening against two microbial strains bacterium SA (Staphylococcus aureus) and, fungal CA (Candida albicans). The MIC values of SA and CA were 35.34 and 47.80 mg/mL for NFE, 117.40 and 108.01 mg/mL for NFM, respectively. Further on, cell viability assay showed that IC50 values of extract NFE and NFM on human UMUC-3 bladder carcinogenic cells were 865.1 and 789.1 µg/mL with less effect to human SVHUC-1 normal cell line for 72hr incubation. Using UPLC-Q-exactive Orbitrap-MS/MS, ten compounds were identified in the noni extracts and confirmed from the HMDB and FooDB. Five known bioactive compounds had been used for treatments in anti-cancer, anti-obesity, and Covid-19 patients. The remaining five compounds were found novel in noni fruit. They were Cyanidin 3-(2 G-xylosylrutinoside), Inulobiose, Clausarinol, Pectachol, and 4,7-Megastigmadien-9-ol. The potential bioactivities of these novel compounds will be studied in the near future. These findings form a basis on screening natural medicinal plant extracts for beneficial use as a food and health source.


Subject(s)
Antineoplastic Agents , COVID-19 , Morinda , Anti-Bacterial Agents , Antineoplastic Agents/pharmacology , Ethanol , Fruit , Humans , Methanol , Plant Extracts/pharmacology , Solvents , Tandem Mass Spectrometry
4.
Int J Biol Macromol ; 219: 414-427, 2022 Oct 31.
Article in English | MEDLINE | ID: covidwho-1977348

ABSTRACT

Guanine-rich DNA sequences may fold back into non-canonical four-stranded secondary structures termed as G-quadruplexes. The role of G-quadruplexes has already been well established in different diseases like cancer, neurological and viral disorders etc. Also, several small molecules have been reported, which can influence the involvement of G-quadruplexes either through stabilization or destabilization in the cellular environment. Growing statistics have associated G-quadruplex assemblies to a discrete biological process in vivo, including DNA replication, transcription, genomic stability, and epigenetic regulation. DNA G-quadruplex existence in human telomere is well recognized attractive target for anticancer drugs. G-quadruplex-interactive ligands have been known to prevent telomerase access as well as telomere capping. To the best of our understanding, the role of G-quadruplexes in virology, neuropharmacology, cancer progression and its treatment has not been discussed on a single platform till date. This review aims to enhance our knowledge regarding these magical sticky quadruplex structures, which have been quite significantly proved to be the part of many cellular processes along with their established in vivo existence. Understanding regarding stabilizing or destabilizing ligands of these multistranded guanine quadruplex structures might be proved as the facilitator of drug discovery process for many incurable diseases in future.


Subject(s)
Antineoplastic Agents , G-Quadruplexes , Telomerase , Antineoplastic Agents/pharmacology , DNA/chemistry , Epigenesis, Genetic , Guanine/chemistry , Humans , Ligands , Telomerase/chemistry , Telomere/genetics , Telomere/metabolism
5.
Microb Pathog ; 169: 105615, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1946063

ABSTRACT

Herein we have selected seventeen anti-lung cancer drugs to screen against Mpro, PLpro and spike glycoproteins of SARS-CoV-2to ascertain the potential therapeutic agent against COVID-19. ADMET profiling were employed to evaluate their pharmacokinetic properties. Molecular docking studies revealed that Capmatinib (CAP) showed highest binding affinity against the selected proteins of SARS-CoV-2. Molecular Dynamics (MD) simulation and the analysis of RMSD, RMSF, and binding energy confirmed the abrupt conformational changes of the proteins due to the presence of this drug. These findings provide an opportunity for doing advanced experimental research to evaluate the potential drug to combat COVID-19.


Subject(s)
Antineoplastic Agents , COVID-19 , Neoplasms , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , SARS-CoV-2
6.
Chem Biol Interact ; 363: 110025, 2022 Aug 25.
Article in English | MEDLINE | ID: covidwho-1906835

ABSTRACT

In order to discover new dual-active agents, a series of novel Biginelli hybrids (tetrahydropyrimidines) and their ruthenium(II) complexes were synthesized. Newly synthesized compounds were characterized by IR, NMR, and X-ray techniques and investigated for their cytotoxic effect on human cancer cell lines HeLa, LS174, A549, A375, K562 and normal fibroblasts (MRC-5). For further examination of the cytotoxic mechanisms of novel complexes, two of them were chosen for analyzing their effects on the distribution of HeLa cells in the cell cycle phases. The results of the flow cytometry analysis suggest that the proportion of cells in G2/M phase was decreased following the increase of subG1 phase in all treatments. These results confirmed that cells treated with 5b and 5c were induced to undergo apoptotic death. The ruthenium complexes 5a-5d show significant inhibitory potency against SARS-CoV-2 Mpro. Therefore, molecule 5b has significance, while 5e possesses the lowest values of ΔGbind and Ki, which are comparable to cinanserin, and hydroxychloroquine. In addition, achieved results will open a new avenue in drug design for more research on the possible therapeutic applications of dual-active Biginelli-based drugs (anticancer-antiviral). Dual-active drugs based on the hybridization concept "one drug curing two diseases" could be a successful tactic in healing patients who have cancer and the virus SARS-CoV-2 at the same time.


Subject(s)
Antineoplastic Agents , COVID-19 , Coordination Complexes , Ruthenium , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Cell Line, Tumor , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Ruthenium/chemistry , Ruthenium/pharmacology , SARS-CoV-2
7.
Pharmacol Res Perspect ; 9(3): e00800, 2021 05.
Article in English | MEDLINE | ID: covidwho-1898944

ABSTRACT

Antiprotozoal drug nitazoxanide (NTZ) has shown diverse pharmacological properties and has appeared in several clinical trials. Herein we present the synthesis, characterization, in vitro biological investigation, and in silico study of four hetero aryl amide analogs of NTZ. Among the synthesized molecules, compound 2 and compound 4 exhibited promising antibacterial activity against Escherichia coli (E. coli), superior to that displayed by the parent drug nitazoxanide as revealed from the in vitro antibacterial assay. Compound 2 displayed zone of inhibition of 20 mm, twice as large as the parent drug NTZ (10 mm) in their least concentration (12.5 µg/ml). Compound 1 also showed antibacterial effect similar to that of nitazoxanide. The analogs were also tested for in vitro cytotoxic activity by employing cell counting kit-8 (CCK-8) assay technique in HeLa cell line, and compound 2 was identified as a potential anticancer agent having IC50 value of 172 µg which proves it to be more potent than nitazoxanide (IC50  = 428 µg). Furthermore, the compounds were subjected to molecular docking study against various bacterial and cancer signaling proteins. The in vitro test results corroborated with the in silico docking study as compound 2 and compound 4 had comparatively stronger binding affinity against the proteins and showed a higher docking score than nitazoxanide toward human mitogen-activated protein kinase (MAPK9) and fatty acid biosynthesis enzyme (FabH) of E. coli. Moreover, the docking study demonstrated dihydrofolate reductase (DHFR) and thymidylate synthase (TS) as probable new targets for nitazoxanide and its synthetic analogs. Overall, the study suggests that nitazoxanide and its analogs can be a potential lead compound in the drug development.


Subject(s)
Amides , Anti-Bacterial Agents , Antineoplastic Agents , Antiparasitic Agents , Nitro Compounds , Thiazoles , Amides/chemistry , Amides/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Bacterial Proteins/metabolism , Biological Assay , Cell Survival/drug effects , Escherichia coli/drug effects , Escherichia coli/growth & development , HeLa Cells , Humans , Mitogen-Activated Protein Kinase 9/metabolism , Molecular Docking Simulation , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Tetrahydrofolate Dehydrogenase/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Thymidylate Synthase/metabolism
8.
Viruses ; 14(3)2022 03 03.
Article in English | MEDLINE | ID: covidwho-1732235

ABSTRACT

Rocaglates are potent broad-spectrum antiviral compounds with a promising safety profile. They inhibit viral protein synthesis for different RNA viruses by clamping the 5'-UTRs of mRNAs onto the surface of the RNA helicase eIF4A. Apart from the natural rocaglate silvestrol, synthetic rocaglates like zotatifin or CR-1-31-B have been developed. Here, we compared the effects of rocaglates on viral 5'-UTR-mediated reporter gene expression and binding to an eIF4A-polypurine complex. Furthermore, we analyzed the cytotoxicity of rocaglates on several human immune cells and compared their antiviral activities in coronavirus-infected cells. Finally, the potential for developing viral resistance was evaluated by passaging human coronavirus 229E (HCoV-229E) in the presence of increasing concentrations of rocaglates in MRC-5 cells. Importantly, no decrease in rocaglate-sensitivity was observed, suggesting that virus escape mutants are unlikely to emerge if the host factor eIF4A is targeted. In summary, all three rocaglates are promising antivirals with differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. In detail, zotatifin showed reduced RNA-clamping efficiency and antiviral activity compared to silvestrol and CR-1-31-B, but was less cytotoxic for immune cells. Our results underline the potential of rocaglates as broad-spectrum antivirals with no indications for the emergence of escape mutations in HCoV-229E.


Subject(s)
Antineoplastic Agents , Coronavirus , 5' Untranslated Regions , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , Constriction , Humans
9.
Molecules ; 27(4)2022 Feb 09.
Article in English | MEDLINE | ID: covidwho-1715565

ABSTRACT

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7-18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.


Subject(s)
Antineoplastic Agents , Chalcones , Cyclooxygenase 2 Inhibitors , Neoplasm Proteins , Neoplasms , Protein Kinase Inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chalcones/chemical synthesis , Chalcones/chemistry , Chalcones/pharmacology , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , Humans , Molecular Structure , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms/drug therapy , Neoplasms/enzymology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology
10.
Pharmacol Res ; 178: 106138, 2022 04.
Article in English | MEDLINE | ID: covidwho-1693034

ABSTRACT

Licorice (Glycyrrhiza glabra) is a well-known natural herb used to treat different ailments since ancient times. Glycyrrhizin (GL), which is the primary triterpenoid compound of licorice extract, has been known to have broad-spectrum pharmacological effects. GL is cleaved into glucuronide and the aglycone, glycyrrhetinic acid (GA), which exists in two stereoisomeric forms: 18α- and 18ß-GA. It is well documented that GL and GA have great potential as anti-inflammatory, anticancer, antiviral, anti-diabetic, antioxidant, and hepatoprotective agents. Studies undertaken during the coronavirus disease 2019 pandemic suggest that GL is effective at inhibiting the viral replication of severe acute respiratory syndrome coronavirus 2. The anticancer effects of GL and GA involve modulating various signaling pathways, such as the phosphatase and tensin homolog/phosphatidylinositol 3-kinase/protein kinase B pathway, the mitogen-activated protein kinase, and the mammalian target of rapamycin/signal transducer and activator of transcription 3, which are mainly involved in regulating cancer cell death, oxidative stress, and inflammation. The potential of GL and GA in preventing cancer development and suppressing the growth and invasion of different cancer types has been reviewed in this paper. This review also provides molecular insights on the mechanism of action for the oncopreventive and oncotherapeutic effects of GL and its derivative, GA, which could help develop more specific forms of these agents for clinical use.


Subject(s)
Antineoplastic Agents , COVID-19 , Glycyrrhiza , Triterpenes , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Glycyrrhizic Acid/pharmacology , Glycyrrhizic Acid/therapeutic use , Humans , Phytochemicals , Plant Extracts , Triterpenes/pharmacology , Triterpenes/therapeutic use
11.
Molecules ; 27(3)2022 Jan 28.
Article in English | MEDLINE | ID: covidwho-1686898

ABSTRACT

Cancer is the second most fatal disease worldwide, with colon cancer being the third most prevalent and fatal form of cancer in several Western countries. The risk of acquisition of resistance to chemotherapy remains a significant hurdle in the management of various types of cancer, especially colon cancer. Therefore, it is essential to develop alternative treatment modalities. Naturally occurring alkaloids have been shown to regulate various mechanistic pathways linked to cell proliferation, cell cycle, and metastasis. This review aims to shed light on the potential of alkaloids as anti-colon-cancer chemotherapy agents that can modulate or arrest the cell cycle. Preclinical investigated alkaloids have shown anti-colon cancer activities and inhibition of cancer cell proliferation via cell cycle arrest at different stages, suggesting that alkaloids may have the potential to act as anticancer molecules.


Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Cycle Checkpoints/drug effects , Colonic Neoplasms/drug therapy , Alkaloids/therapeutic use , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Proliferation/drug effects , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Drug Discovery , Humans
12.
Chem Soc Rev ; 51(4): 1212-1233, 2022 Feb 21.
Article in English | MEDLINE | ID: covidwho-1661982

ABSTRACT

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances.


Subject(s)
Antineoplastic Agents , COVID-19 , Neoplasms , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Humans , Immunogenic Cell Death , Immunotherapy , Neoplasms/therapy , Pandemics , SARS-CoV-2
13.
Int J Mol Sci ; 23(2)2022 Jan 13.
Article in English | MEDLINE | ID: covidwho-1637017

ABSTRACT

Malignant melanoma is still a serious medical problem. Relatively high mortality, a still-growing number of newly diagnosed cases, and insufficiently effective methods of therapy necessitate melanoma research. Tetracyclines are compounds with pleiotropic pharmacological properties. Previously published studies on melanotic melanoma cells ascertained that minocycline and doxycycline exerted an anti-melanoma effect. The purpose of the study was to assess the anti-melanoma potential and mechanisms of action of minocycline and doxycycline using A375 and C32 human amelanotic melanoma cell lines. The obtained results indicate that the tested drugs inhibited proliferation, decreased cell viability, and induced apoptosis in amelanotic melanoma cells. The treatment caused changes in the cell cycle profile and decreased the intracellular level of reduced thiols and mitochondrial membrane potential. The exposure of A375 and C32 cells to minocycline and doxycycline triggered the release of cytochrome c and activated initiator and effector caspases. The anti-melanoma effect of analyzed drugs appeared to be related to the up-regulation of ERK1/2 and MITF. Moreover, it was noticed that minocycline and doxycycline increased the level of LC3A/B, an autophagy marker, in A375 cells. In summary, the study showed the pleiotropic anti-cancer action of minocycline and doxycycline against amelanotic melanoma cells. Considering all results, it could be concluded that doxycycline was a more potent drug than minocycline.


Subject(s)
Antineoplastic Agents/pharmacology , Doxycycline/pharmacology , Minocycline/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Biomarkers, Tumor , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Melanoma, Amelanotic , Membrane Potential, Mitochondrial/drug effects
14.
Biosci Rep ; 41(12)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1592575

ABSTRACT

Parasporin-2Aa1 (PS2Aa1) is a toxic protein of 37 KDa (30 kDa, activated form produced by proteolysis) that was shown to be cytotoxic against specific human cancer cells, although its mechanism of action has not been elucidated yet. In order to study the role of some native peptide fragments of proteins on anticancer activity, here we investigated the cytotoxic effect of peptide fragments from domain-1 of PS2Aa1 and one of the loops present in the binding region of the virus spike protein from Alphacoronavirus (HCoV-229E), the latter according to scientific reports, who showed interaction with the human APN (h-APN) receptor, evidence corroborated through computational simulations, and thus being possible active against colon cancer cells. Peptides namely P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa were synthesized using the Fmoc solid-phase synthesis and characterized by mass spectrometry (MS). Additionally, one region from loop 1 of HCoV-229E, Loop1-HCoV-229E, was also synthesized and characterized. The A4W-GGN5 anticancer peptide and 5-fluorouracil (5-FU) were taken as a control in all experiments. Circular dichroism revealed an α-helix structure for the peptides derived from PS2Aa1 (P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa) and ß-laminar structure for the peptide derived from Alphacoronavirus spike protein Loop1-HCoV-229E. Peptides showed a hemolysis percentage of less than 20% at 100 µM concentration. Besides, peptides exhibited stronger anticancer activity against SW480 and SW620 cells after exposure for 48 h. Likewise, these compounds showed significantly lower toxicity against normal cells CHO-K1. The results suggest that native peptide fragments from Ps2Aa1 may be optimized as a novel potential cancer-therapeutic agents.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Endotoxins/pharmacology , Peptide Fragments/pharmacology , Spike Glycoprotein, Coronavirus/pharmacology , Alphacoronavirus , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , CD13 Antigens/metabolism , CHO Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cricetulus , Endotoxins/toxicity , Hemolysis/drug effects , Humans , Molecular Docking Simulation , Peptide Fragments/chemical synthesis , Peptide Fragments/toxicity , Protein Conformation, alpha-Helical , Sheep, Domestic , Spike Glycoprotein, Coronavirus/toxicity , Structure-Activity Relationship
15.
J Inorg Biochem ; 228: 111691, 2022 03.
Article in English | MEDLINE | ID: covidwho-1558451

ABSTRACT

Zinc can play a pathophysiological role in several diseases and can interfere in key processes of microbial growth. This evidence justifies the efforts in applying Zinc ionophores to restore Zinc homeostasis and treat bacterial/viral infections such as coronavirus diseases. Zinc ionophores increase the intracellular concentration of Zinc ions causing significant biological effects. This review provides, for the first time, an overview of the applications of the main Zinc ionophores in Zinc deficiency, infectious diseases, and in cancer, discussing the pharmacological and coordination properties of the Zinc ionophores.


Subject(s)
Communicable Diseases/drug therapy , Ionophores/chemistry , Neoplasms/drug therapy , Zinc/chemistry , Zinc/pharmacology , Acrodermatitis/drug therapy , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Homeostasis/drug effects , Humans , Ionophores/pharmacology , Zinc/deficiency
16.
Carbohydr Polym ; 285: 118971, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1549670

ABSTRACT

Ligusticum chuanxiong, the dried rhizome of Ligusticum chuanxiong Hort, has been widely applied in traditional Chinese medicine for treating plague, and it has appeared frequently in the prescriptions against COVID-19 lately. Ligusticum chuanxiong polysaccharide (LCPs) is one of the effective substances, which has various activities, such as, anti-oxidation, promoting immunity, anti-tumor, and anti-bacteria. The purified fractions of LCPs are considered to be pectic polysaccharides, which are mainly composed of GalA, Gal, Ara and Rha, and are generally linked by α-1,4-d-GalpA, α-1,2-l-Rhap, α-1,5-l-Araf, ß-1,3-d-Galp and ß-1,4-d-Galp, etc. The pectic polysaccharide shows an anti-infective inflammatory activity, which is related to antiviral infection of Ligusticum chuanxiong. In this article, the isolation, purification, structural features, and biological activities of LCPs in recent years are reviewed, and the potential of LCPs against viral infection as well as questions that need future research are discussed.


Subject(s)
COVID-19/drug therapy , Ligusticum/chemistry , Polysaccharides/chemistry , Polysaccharides/pharmacology , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/virology , Carbohydrate Conformation , Carbohydrate Sequence , Drugs, Chinese Herbal , Humans , Polysaccharides/isolation & purification , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
17.
Int J Mol Sci ; 22(23)2021 Nov 30.
Article in English | MEDLINE | ID: covidwho-1542586

ABSTRACT

Compounds of natural origin, an infinite treasure of bioactive chemical entities, persist as an inexhaustible resource for discovering new medicines. In this review, we summarize the naturally occurring ellagitannins, sanguiins, which are bioactive constituents of various traditional medicinal plants, especially from the Rosaceae family. In-depth studies of sanguiin H-6 as an antimicrobial, antiviral, anticancer, anti-inflammatory, and osteoclastogenesis inhibitory agent have led to potent drug candidates. In addition, recently, virtual screening studies have suggested that sanguiin H-6 might increase resistance toward SARS-CoV-2 in the early stages of infection. Further experimental investigations on ADMET (absorption, distribution, metabolism, excretion, and toxicity) supplemented with molecular docking and molecular dynamics simulation are still needed to fully understand sanguiins' mechanism of action. In sum, sanguiins appear to be promising compounds for additional studies, especially for their application in therapies for a multitude of common and debilitating ailments.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Hydrolyzable Tannins/chemistry , Hydrolyzable Tannins/pharmacology , Animals , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , COVID-19/drug therapy , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Pharmacokinetics , Rosaceae/chemistry , SARS-CoV-2/drug effects
18.
ESMO Open ; 7(1): 100350, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1536535

ABSTRACT

BACKGROUND: Preliminary analysis from the Vax-On study did not find a correlation between cancer treatment type and antibody response to COVID-19 vaccination. We carried out a secondary subgroup analysis to verify the effects of comprehensive cancer treatment classification on vaccine immunogenicity. METHODS: The Vax-On study prospectively enrolled patients who started a two-dose messenger RNA-BNT162b2 vaccine schedule from 9 March 2021 to 12 April 2021 (timepoint-1). Those on active treatment within the previous 28 days accounted for the exposed cases. Patients who had discontinued such treatment by at least 28 days or received intravesical therapy represented the control cases. Quantification of immunoglobulin G (IgG) antibodies against the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein was carried out before the second dose (timepoint-2) and 8 weeks thereafter (timepoint-3). Seroconversion response was defined at ≥50 arbitrary units/ml IgG titer. Classification of antineoplastic agents was based on their pharmacodynamic properties. RESULTS: Three hundred and sixty-six patients were enrolled (86 and 260 as control and exposed cases, respectively). Univariate analysis revealed a significantly lower IgG titer after both doses of vaccine in subgroups treated with tyrosine kinase inhibitors (TKIs), multiple cytotoxic agents, alkylating agents, and topoisomerase inhibitors. At timepoint-3, seroconversion response was significantly impaired in the topoisomerase inhibitors and mechanistic target of rapamycin (mTOR) inhibitors subgroups. After multivariate testing, treatment with alkylating agents and TKIs was significantly associated with a reduced change in IgG titer at timepoint-2. Treatment with mTOR inhibitors resulted in a similar interaction at each timepoint. Cyclin-dependent kinase 4/6 inhibitor treatment was independently correlated with an incremental variation in IgG titer at timepoint-3. Specific subgroups (TKIs, antimetabolites, alkylating agents, and multiple-agent chemotherapy) predicted lack of seroconversion at timepoint-2, but their effect was not retained at timepoint-3. Eastern Cooperative Oncology Group performance status 2, immunosuppressive corticosteroid dosing, and granulocyte colony-stimulating factor use were independently linked to lower IgG titer after either dose of vaccine. CONCLUSIONS: Drugs interfering with DNA synthesis, multiple-agent cytotoxic chemotherapy, TKIs, mTOR and cyclin-dependent kinase 4/6 inhibitors differentially modulate humoral response to messenger RNA-BNT162b2 vaccine.


Subject(s)
Antineoplastic Agents , COVID-19 , Immunity, Humoral , Immunogenicity, Vaccine , Neoplasms , Spike Glycoprotein, Coronavirus , Antibodies, Viral/blood , Antineoplastic Agents/pharmacology , COVID-19/prevention & control , Humans , Immunity, Humoral/drug effects , Immunoglobulin G/blood , Neoplasms/drug therapy , Neoplasms/immunology , Prospective Studies , RNA, Messenger/genetics , RNA, Messenger/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
19.
Curr Oncol Rep ; 23(11): 134, 2021 10 22.
Article in English | MEDLINE | ID: covidwho-1530397

ABSTRACT

PURPOSE OF REVIEW: Since the past year, the fast spread of coronavirus disease 2019 (COVID-19) has represented a global health threat, especially for cancer patients, that has required an urgent reorganization of clinical activities. Here, we will critically revise the profound impact that the pandemic has generated in lung cancer patients, as well the most significant challenges that oncologists have to face to maintain the highest possible standards in the management of lung cancer patients in the pandemic era. RECENT FINDINGS: Evidences suggested a higher susceptibility and mortality of lung cancer patients due to COVID-19. The hard management of this patient population has been also due to the potential cross interference of anti-tumor drugs on SARS-Cov-2 infection and to the differential diagnosis between COVID-19 pneumonitis and drug-related pneumonitis. COVID-19 pandemic has generated a profound reshaping of oncological activities and the development of recommendations by the oncology scientific community to prioritize anti-tumor treatments for lung cancer patients.


Subject(s)
COVID-19/complications , COVID-19/mortality , Lung Neoplasms/complications , Lung Neoplasms/mortality , Pneumonia/diagnosis , Antineoplastic Agents/pharmacology , COVID-19 Vaccines , Comorbidity , Diagnosis, Differential , Humans , Medical Oncology/methods , Pandemics , Risk Factors , SARS-CoV-2 , Tomography, X-Ray Computed
20.
Int J Mol Sci ; 22(22)2021 Nov 16.
Article in English | MEDLINE | ID: covidwho-1534087

ABSTRACT

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.


Subject(s)
Antineoplastic Agents/pharmacology , Apolipoproteins E/genetics , Bexarotene/pharmacology , Leukocytes/drug effects , Nicotinic Acids/pharmacology , Retinoid X Receptor alpha/agonists , Animals , Antineoplastic Agents/chemical synthesis , Apolipoproteins E/metabolism , Bexarotene/analogs & derivatives , Bexarotene/chemical synthesis , Cell Line, Tumor , Dose-Response Relationship, Drug , Gene Expression , Humans , Leukocytes/metabolism , Leukocytes/pathology , Nicotinic Acids/chemical synthesis , Retinoid X Receptor alpha/genetics , Retinoid X Receptor alpha/metabolism , Structure-Activity Relationship
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