Gold compounds have a long history of use in medicine. Auranofin was developed more than 30 years ago as an oral therapy for rheumatoid arthritis. Now, however, auranofin is rarely used in clinical ...practice despite its efficacy for treating rheumatoid arthritis because more novel antirheumatic medications are available. Although its use in clinical practice has decreased, studies on auranofin have continued and it shows promise for the treatment of several different diseases, including cancer and bacterial and parasitic infections. Several potential novel applications of auranofin for treating human disease have been proposed. Auranofin inhibits the activity of thioredoxin reductase (TrxR), an enzyme of the thioredoxin (Trx) system that is important for maintaining the intracellular redox state. Particularly in cancers, TrxR inhibition leads to an increase in cellular oxidative stress and induces apoptosis. TrxR overexpression is associated with aggressive tumor progression and poor survival in patients with breast, ovarian, and lung cancers. The Trx system may represent an attractive target for the development of new cancer treatments. Therefore, the TrxR inhibitor auranofin may be a potent anticancer agent. This review summarizes the current understanding of auranofin for cancer therapy.
The tumor microenvironment comprises tumor cells surrounding normal cells and the extracellular matrix. The surrounding normal cells have critical roles in the regulation of growth and metastasis of ...cancers, including the maintenance of cancer stem cells and the formation of cancer metastatic niches. Recent anti-tumor strategies targeting the tumor microenvironment have included inhibition of angiogenesis and the augmentation of immune reactions. However, in this review, we will focus on stromal cells (fibroblast-like cells), a common constituent of the tumor microenvironment. Since stromal cells regulate the growth of cancer cells positively and negatively through adhesion and secreted factors, anti-tumor strategies should consider modulating tumor-stromal cell interactions through use of small molecules.
Background
This review focuses on exosomes derived from various cancer cells. The review discusses the possibility of differentiating macrophages in alternatively activated anti-inflammatory ...pro-tumorigenic M2 macrophage phenotypes and classically activated pro-inflammatory, anti-tumorigenic M1 macrophage phenotypes in the tumor microenvironment (TME). The review is divided into two main parts, as follows: (1) role of exosomes in alternatively activating M2-like macrophages-breast cancer-derived exosomes, hepatocellular carcinoma (HCC) cell-derived exosomes, lung cancer-derived exosomes, prostate cancer-derived exosomes, Oral squamous cell carcinoma (OSCC)—derived exosomes, epithelial ovarian cancer (EOC)—derived exosomes, Glioblastoma (GBM) cell-derived exosomes, and colorectal cancer-derived exosomes, (2) role of exosomes in classically activating M1-like macrophages, oral squamous cell carcinoma-derived exosomes, breast cancer-derived exosomes, Pancreatic-cancer derived modified exosomes, and colorectal cancer-derived exosomes, and (3) exosomes and antibody-dependent cellular cytotoxicity (ADCC). This review addresses the following subjects: (1) crosstalk between cancer-derived exosomes and recipient macrophages, (2) the role of cancer-derived exosome payload(s) in modulating macrophage fate of differentiation, and (3) intracellular signaling mechanisms in macrophages regarding the exosome’s payload(s) upon its uptake and regulation of the TME.
Evidence
Under the electron microscope, nanoscale exosomes appear as specialized membranous vesicles that emerge from the endocytic cellular compartments. Exosomes harbor proteins, growth factors, cytokines, lipids, miRNA, mRNA, and DNAs. Exosomes are released by many cell types, including reticulocytes, dendritic cells, B-lymphocytes, platelets, mast cells, and tumor cells. It is becoming clear that exosomes can impinge upon signal transduction pathways, serve as a mediator of signaling crosstalk, thereby regulating cell-to-cell wireless communications.
Conclusion
Based on the vesicular cargo, the molecular constituents, the exosomes have the potential to change the fate of macrophage phenotypes, either M1, classically activated macrophages, or M2, alternatively activated macrophages. In this review, we discuss and describe the ability of tumor-derived exosomes in the mechanism of macrophage activation and polarization.
Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with ...metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab, were developed. The use of targeted drugs in clinical practice has significantly increased patients' overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment. Therapeutic strategies are continually being updated to select the most suitable targeted drugs based on the results of clinical trials that are currently underway. This review discusses the up-to date molecular evidence of targeted therapy for mCRC and summarizes the Food and Drug Administration-approved targeted drugs including the results of clinical trials. We also explain their mechanisms of action and how these affect the choice of a suitable targeted therapy.
The cellular thermal shift assay (CETSA) has recently been devised as a label-free method for target validation of small compounds and monitoring the thermal stabilization or destabilization of ...proteins due to binding with the compound. Herein, we developed a modified method by combining the CETSA and proteomics analysis based on 2D gel electrophoresis, namely 2DE-CETSA, to identify the thermal stability-shifted proteins by binding with a new compound. We applied the 2DE-CETSA for analysis of a target-unknown compound, NPD10084, which exerts anti-proliferative activity against colorectal cancer cells in vitro and in vivo, and identified pyruvate kinase muscle isoform 2 (PKM2) as a candidate target protein. Interestingly, NPD10084 interrupted protein-protein interactions between PKM2 and β-catenin or STAT3, with subsequent suppression of downstream signaling. We thus demonstrate that our 2DE-CETSA method is applicable for identification of target compounds discovered by phenotypic screening.
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•2D gel electrophoresis-based proteome-wide CETSA, namely 2DE-CETSA, was developed•Cell-based screening identified NPD10084 as an anti-cancer compound•Analysis by 2DE-CETSA revealed thermal destabilization of PKM2 by NPD10084•NPD10084 suppressed non-glycolytic PKM2-regulated signaling in cancer cells
Nagasawa et al. developed a proteome-wide cellular thermal shift assay (CETSA) method “2DE-CETSA” to identify thermal stability-shifted proteins due to interactions with a small compound. Using 2DE-CETSA, they have shown that an anti-cancer compound NPD10084 induced thermal destabilization of PKM2. NPD10084 disrupted the PKM2 complex and inhibited downstream signaling.
When screening active compounds by phenotypic assays, we often encounter mitochondrial toxins, which are compounds that can affect mitochondrial functions. In normal cells, these toxins may have ...relatively low toxicity but can nonetheless show measurable effects even at low concentrations. On the other hand, in animals, mitochondrial toxins can exert severe toxicity. Mitochondrial toxins that act as inhibitors of respiratory chain complexes in oxidative phosphorylation (OXPHOS) are typically avoided during drug discovery efforts, as such compounds can directly promote lethal inhibition of pulmonary respiration. However, mitochondrial toxins could in fact have beneficial therapeutic effects. Anti-cancer strategies that target mitochondrial functions, particularly OXPHOS, have received increasing attention in recent years. In this review article we examine the significance of OXPHOS inhibitors as anti-cancer drug candidates and discuss compounds having microbial origins.
New three macrocyclic diolides, named bispolides C-E (1-3), were isolated from a fermentation broth of the actinomycete strain MG372-hF19, which produces an indole glycoside and leptomycins as we ...reported previously. The absolute structures of compounds 1-3 were elucidated by NMR and X-ray crystallography. Compounds 1-3 diverge from the known nine bispolides in their different alkylation patterns on the 20-membered macrocyclic diolide skeleton and the side chain in their planar structures. Furthermore, compounds 1-3 exhibited antibacterial activity against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci and cytotoxic activity against human cancer cell lines. Among them, compound 3 has the most potent biological activities against bacteria and tumor cells. Additionally, using a membrane-potential-sensitive fluorescence probe, we found that compounds 1-3 and elaiophylin have a similar effect on membrane potential in A549 human lung cancer cells.
Structure-activity relationship study of leucinostatin A, a natural nonapeptide, was performed to gain insight into the structural requirements for leucinostatin A to exhibit antiproliferative ...activity against DU-145 prostate cancer cells under cocultured conditions with the corresponding stromal cells. Twenty truncated peptide analogs of leucinostatin A revealed that the nonapeptide structure as a whole is essential for the biological activity. Alanine scanning demonstrated the importance of some of the amino acid components, including hydroxyleucine and the second leucine from the N-terminus. Two of the three aminoisobutyric acids could be substituted with one of the enantiomers of alanine, clearly demonstrating that each methyl group in these portions has a distinct influence on the growth-inhibitory activity.
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A novel Vibrio strain, JCM 31412T, was isolated from seawater collected from the Inland Sea (Setonaikai), Japan, and characterized as a Gram-negative, oxidase-positive, catalase-negative, ...facultatively anaerobic, motile, ovoid-shaped bacterium with one polar flagellum. Based on 16S rDNA gene identity, strain JCM 31412T showed a close relationship with type strains of Vibrio brasiliensis (LMG 20546T, 98.2% identity), V. harveyi (NBRC 15634T, 98.2%), V. caribbeanicus (ATCC BAA-2122T, 97.8%) and V. proteolyticus (NBRC 13287T, 97.8%). The G+C content of strain JCM 31412T DNA was 46.8%. Multi-locus sequence analysis (MLSA) of eight loci (ftsZ, gapA, gyrB, mreB, pyrH, recA, rpoA and topA; 5535bp) further clustered strain JCM 31412T in the Nereis clade, genus Vibrio. Phenotypically, strain JCM 31412T differed from the closest related Vibrio species in its utilization of melibiose and raffinose, and its lack of casein and gelatin hydrolysis. It was further differentiated based on its fatty acid composition, specifically properties of C12:03OH and summed features, which were significantly different from those of V. brasiliensis, V. nigripulchritudo and V. caribbeanicus type strains. Overall, the results of DNA-DNA hybridization, and physiological and biochemical analysis differentiated strain JCM 31412T from other described species of the genus Vibrio. Based on these polyphasic taxonomic findings, it was therefore concluded that JCM 31412T was a novel Vibrio species, for which the name Vibrio japonicus sp. nov. was proposed, with JCM 31412T (= LMG 29636T = ATCC TSD-62T) as the type strain.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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