Shikonin, an inhibitor of inflammasomes, inhibits Epstein-Barr virus reactivation.

Epstein-Barr virus (EBV) is a highly prevalent human herpesvirus that persists for life in more than 95% of the adult population. EBV usually establishes an asymptomatic life-long infection, but it is also associated with malignancies affecting B lymphocytes and epithelial cells mainly. The virus alternates between a latent phase and a lytic phase, both of which contribute to the initiation of the tumor process.

Diphenyl ditelluride anticancer activity and DNA topoisomerase I poisoning in human colon cancer HCT116 cells.

Diphenyl ditelluride (DPDT) is an organotellurium (OT) compound with pharmacological properties, including antioxidant, antigenotoxic and antimutagenic activities when applied at low concentrations. However, DPDT as well as other OT compounds also show cytotoxicity against mammalian cells when treatments occur at higher drug concentrations. Considering that the underlying mechanisms of toxicity of DPDT against tumor cells have been poorly explored, the objective of our study was to investigate the effects of DPDT against both human cancer and non-tumorigenic cells.

The C-Terminal Acidic Tail Modulates the Anticancer Properties of HMGB1.

Energy metabolism reprogramming was recently listed as a hallmark of cancer. In this process, the switch from pyruvate kinase isoenzyme type M1 to pyruvate kinase isoenzyme type M2 (PKM2) is believed to play a crucial role. Interestingly, the activity of the active form of PKM2 can efficiently be inhibited by the high-mobility group box 1 (HMGB1) protein, leading to a rapid blockage of glucose-dependent aerobic respiration and cancer cell death.

Expression Pattern of Purinergic Signaling Components in Colorectal Cancer Cells and Differential Cellular Outcomes Induced by Extracellular ATP and Adenosine.

The purine nucleotide adenosine triphosphate (ATP) is known for its fundamental role in cellular bioenergetics. However, in the last decades, different works have described emerging functions for ATP, such as that of a danger signaling molecule acting in the extracellular space on both tumor and stromal compartments. Beside its role in immune cell signaling, several studies have shown that high concentrations of extracellular ATP can directly or indirectly act on cancer cells.

Distinction between 2'- and 3'-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration.

Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2'- and 3'-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2'- and 3'-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging.

Colorectal Cancer and Immunity: From the Wet Lab to Individuals.

Immunotherapy is a very promising field of research and application for treating cancers, in particular for those that are resistant to chemotherapeutics. Immunotherapy aims at enhancing immune cell activation to increase tumor cells recognition and killing. However, some specific cancer types, such as colorectal cancer (CRC), are less responsive than others to the current immunotherapies.

Cytotoxic constituents from the wheat plant pathogen SN15.

Microbial natural products are continuing to be a promising platform for future drug lead discover. As a part of our ongoing research program on fungal natural product, herein we report metabolites isolated from the fungus SN15 a pathogen of wheat and related cereals. Its chemical investigation led to the purification of new isoleucinic acid derivatives (-) along with the procuramine ().

Secondary Metabolites from the Culture of the Marine-derived Fungus PC 362H and Evaluation of the Anticancer Activity of Its Metabolite Hyalodendrin.

High-throughput screening assays have been designed to identify compounds capable of inhibiting phenotypes involved in cancer aggressiveness. However, most studies used commercially available chemical libraries. This prompted us to explore natural products isolated from marine-derived fungi as a new source of molecules.

Epstein-Barr Virus BALF0 and BALF1 Modulate Autophagy.

Autophagy is an essential catabolic process that degrades cytoplasmic components within the lysosome, therefore ensuring cell survival and homeostasis. A growing number of viruses, including members of the Herpesviridae family, have been shown to manipulate autophagy to facilitate their persistence or optimize their replication. Previous works showed that the Epstein-Barr virus (EBV), a human transforming gammaherpesvirus, hijacked autophagy during the lytic phase of its cycle, possibly to favor the formation of viral particles.

Dipyridamole as a new drug to prevent Epstein-Barr virus reactivation.

Epstein-Barr virus (EBV) is a widely distributed gamma-herpesvirus that has been associated with various cancers mainly from lymphocytic and epithelial origin. Although EBV-mediated oncogenesis has been associated with viral oncogenes expressed during latency, a growing set of evidence suggested that antiviral treatments directed against EBV lytic phase may contribute to prevent some forms of cancers, including EBV-positive Post-Transplant Lymphoproliferative Diseases. It is shown here that dipyridamole (DIP), a safe drug with favorable and broad pharmacological properties, inhibits EBV reactivation from B-cell lines.

Perspective: plasticity, the enemy of the good.

Plasticity is an important feature of modern cancer research. However, the level at which we should consider it remains an open question. Such debate is not new in the field of cancer and can be exemplified by the different models explaining carcinogenesis.

Detection of IgG directed against a recombinant form of Epstein-Barr virus BALF0/1 protein in patients with nasopharyngeal carcinoma.

BALF0/1 is a putative Epstein-Barr virus (EBV) protein that has been described as a modulator of apoptosis. So far, the lack of specific immunological reagents impaired the detection of native BALF0/1 in EBV-infected cells. This study describes the expression and purification of a truncated form of BALF0/1 (tBALF0) using a heterologous bacterial expression system.

Multifaceted Study on a Cytochalasin Scaffold: Lessons on Reactivity, Multidentate Catalysis, and Anticancer Properties.

An intramolecular Diels-Alder (IMDA) reaction efficiently accelerated by Schreiner's thiourea is reported, to build a functionalized cytochalasin scaffold (periconiasin series) for biological purposes. DFT calculation highlighted a unique multidentate cooperative hydrogen bonding in this catalysis. The deprotection end game afforded a collection of diverse structures and showed the peculiar reactivity of the Diels-Alder cycloadducts upon functionalization.

Intramolecular Aryne-Furan Cycloadditions for the Synthesis of Anticancer Naphthalimides.

An intramolecular aryne Diels-Alder reaction with a furan moiety was applied to the synthesis of dihydrobenzo[ de]isochromenes as intermediates toward naphthalimides. After oxidation, this method offers an efficient approach for the synthesis of substituted naphthalimides, which showed potent cytotoxic activity against HT-29 human cancer cell line.

Combinations of Bevacizumab and Erlotinib Show Activity in Colorectal Cancer Independent of Status.

There is extensive cross-talk between VEGF- and EGFR-pathway signaling in colorectal cancer. However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAb) show disappointing activity, in particular for patients with mutant Previous results show that tyrosine kinase inhibitors (TKI) can be active in colorectal cancer models resistant to mAbs. This prompted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib.

Antimicrobial Oligophenalenone Dimers from the Soil Fungus Talaromyces stipitatus.

New polyketide-derived oligophenalenone dimers, 9a-epi-bacillisporin E (1) and bacillisporins F-H (2-5), along with the known bacillisporin A (6), were isolated from the fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, electronic circular dichroism, and GIAO NMR shift calculation followed by DP4 analysis. The antimicrobial activity of these compounds was evaluated against a panel of human pathogenic bacteria.

Genotype- or Phenotype-Targeting Anticancer Therapies? Lessons from Tumor Evolutionary Biology.

Despite the efficacy of most cancer therapies, drug resistance remains a major problem in the clinic. The eradication of the entire tumor and the cure of the patient by chemotherapy alone are rare, in particular for advanced disease. From an evolutionary perspective, the selective pressure exerted by chemotherapy leads to the emergence of resistant clones where resistance can be associated with many different functional mechanisms at the single cell level or can involve changes in the tumor micro-environment.

Dual inhibition of ATR and ATM potentiates the activity of trabectedin and lurbinectedin by perturbing the DNA damage response and homologous recombination repair.

Trabectedin (Yondelis®, ecteinascidin-743, ET-743) is a marine-derived natural product approved for treatment of advanced soft tissue sarcoma and relapsed platinum-sensitive ovarian cancer. Lurbinectedin is a novel anticancer agent structurally related to trabectedin. Both ecteinascidins generate DNA double-strand breaks that are processed through homologous recombination repair (HRR), thereby rendering HRR-deficient cells particularly sensitive.

Talaroketals A and B, unusual bis(oxaphenalenone) spiro and fused ketals from the soil fungus Talaromyces stipitatus ATCC 10500.

Two novel oxaphenalenone dimers, talaroketals A () and B (), were isolated from the soil fungus Talaromyces stipitatus. Their structures and absolute configurations were determined on the basis of spectroscopic analyses, X-ray diffraction experiments and electronic circular dichroism. Compound () features a rare benzannulated 5,6-spiroketal ring system within the dimeric bis(oxaphenalenone) skeleton while the parent compound () harbors a fused bicyclic furano-pyran moiety.

Unexpected talaroenamine derivatives and an undescribed polyester from the fungus Talaromyces stipitatus ATCC10500.

Chemical investigation of the fungus Talaromyces stipitatus ATCC 10500, whose genome has been sequenced, led to the isolation of four undescribed talaroenamines B-E along with the known talaroenamine A. Their structures were elucidated on the basis of spectroscopic studies including mass spectrometry, extensive 2D NMR and electronic circular dichroism (ECD). Interestingly, talaroenamine A had previously been isolated from the strain of T.

BRCA2 is needed for both repair and cell cycle arrest in mammalian cells exposed to S23906, an anticancer monofunctional DNA binder.

Repair of DNA-targeted anticancer agents is an active area of investigation of both fundamental and clinical interest. However, most studies have focused on a small number of compounds limiting our understanding of both DNA repair and the DNA damage response. S23906 is an acronycine derivative that shows strong activity toward solid tumors in experimental models.

Emergence of drug tolerance in cancer cell populations: an evolutionary outcome of selection, nongenetic instability, and stress-induced adaptation.

In recent experiments on isogenetic cancer cell lines, it was observed that exposure to high doses of anticancer drugs can induce the emergence of a subpopulation of weakly proliferative and drug-tolerant cells, which display markers associated with stem cell-like cancer cells. After a period of time, some of the surviving cells were observed to change their phenotype to resume normal proliferation and eventually repopulate the sample. Furthermore, the drug-tolerant cells could be drug resensitized following drug washout.

Modeling the effects of space structure and combination therapies on phenotypic heterogeneity and drug resistance in solid tumors.

Histopathological evidence supports the idea that the emergence of phenotypic heterogeneity and resistance to cytotoxic drugs can be considered as a process of selection in tumor cell populations. In this framework, can we explain intra-tumor heterogeneity in terms of selection driven by the local cell environment? Can we overcome the emergence of resistance and favor the eradication of cancer cells by using combination therapies? Bearing these questions in mind, we develop a model describing cell dynamics inside a tumor spheroid under the effects of cytotoxic and cytostatic drugs. Cancer cells are assumed to be structured as a population by two real variables standing for space position and the expression level of a phenotype of resistance to cytotoxic drugs.

Intrinsic bevacizumab resistance is associated with prolonged activation of autocrine VEGF signaling and hypoxia tolerance in colorectal cancer cells and can be overcome by nintedanib, a small molecule angiokinase inhibitor.

Colorectal cancer (CRC) is a common tumor type with a high mortality rate, in part due to intrinsic drug resistance. Although bevacizumab, a VEGF-directed neutralizing antibody, is particularly active in this pathology, some patients never respond for reasons not well understood. We here wish to clarify the role of autocrine VEGF signaling in the response of CRC cells to angiogenesis inhibition.

DNA alkylation damage and autophagy induction.

Many alkylating agents are used as chemotherapeutic drugs and have a long history of clinical application. These agents inflict a wide range of DNA damage resulting in a complex cellular response. After DNA damage, cells trigger a series of signaling cascades promoting cellular survival and cell cycle blockage which enables time for DNA repair to occur.