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Rubia plants are one of the most important plant resources possessing significant commercial and medicinal values. Plant endophytes could benefit their host plants in different ways. Rubiaceae-type cyclopeptides (RAs), mainly isolated from Rubia plants, have attracted considerable attentions for their distinctive bicyclic structures and significant antitumor activities, but their contents in plants are low. The aim of this study is to investigate the diversity of endophytic fungi in Rubia plants and their potential for production of RAs. In this work, 143 endophytic fungi isolates were obtained from two Rubia plants. Phylogenetic analysis was performed based on the ITS rDNA sequences, and the isolates were classified into 29 genera. Among them, four endophytic fungal strains were found to produce anti-tumour RAs by LC-MS/MS analysis. This work successfully provides valuable knowledges of endophytic fungi microbiome in Rubia plants for agricultural and industrial applications, and exploits a new environmental-friendly resource of RAs.

Objectives Gastrointestinal cancer, one of the major causes of cancer-related deaths in the world, refers to malignant conditions of the gastrointestinal (GI) tract and other organs. Although conventional therapy has been successful to some extent in cancer treatment, drug resistance and cancer recurrence still limit the therapeutic efficacy. There is increasing evidence indicating that ginsenoside, as a kind of high nutritional value and widely used traditional Chinese medicine, could contribute to the promotion of treatment in GI cancer, which deserves further investigation. Key findings Based on previous studies, the possible mechanisms mainly include regulation of autophagy, apoptosis, proliferation, migration and angiogenesis. However, no studies recently have conducted a more in-depth review of the anti-cancer effects of ginsenoside in GI cancer. Summary Therefore, this review will summarise and analyse the latest developments in the anti-tumour effects of ginsenosides in GI cancer, thus may promote further research of the anti-tumour efficacy of ginsenoside.

BACKGROUND Glioblastoma (GBM) is the most aggressive glial neoplasm characterized by infiltrative cell growth in adults. The current standard of care for high-grade glioma patients includes surgery, radiotherapy and chemotherapy using temozolomide and other alkylating agents. Despite this, median survival of the patients with GBM is less than two years. One of the main factors related to the progression of neoplastic cells is hyperactivity of protein kinases, including CK2 kinase and a high level of tumor hypoxia, both of which also contribute to tumour resistance to treatment. Our previous study indicated that some CK2 inhibitors exhibit anti-proliferative effect on glioma cells. The aim of this study was to examine whether HBO may enhance the anti-tumour efficacy of 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole (TDB) - CK2 inhibitor, under combination HBO/TDB therapy. MATERIAL AND METHODS Studies were performed on human glioblastoma T98G cell line (ATCC). Cells were cultured in MEM medium supplemented with 1-(β-D-2’-deoxyribofuranosyl)-4,5,6,7-tetrabromo-1H-benzimidazole in concentrations of 0.1 μM; 1 μM, 25 μM, 50 μM, 75μM, 100 μM. Cultures were sustained in various oxygen conditions: normoxia for 24 and 48 hours or1 hour of hyperbaric oxygen (HBO, 97,5% O2/2,5% CO2, pressure of 2 ATA) followed by 23 hours of normoxia (21% O2/5% CO2/78% N2). Control groups included the cultures sustained in normoxia conditions. The viability of glioma cell lines was established at 24 and 48 hours post TDB treatment by Cell Titer 96®A Queous One Solution Cell Proliferation Assay. RESULTS The study evidenced that TDB inhibited the viability of neoplastic cells at a concentration of 75 μM after 24 and 48 hours. Administration of hyperbaric oxygen alone also caused a reduction in viability of glioblastoma cells. The cytotoxic effect of the tested CK2 inhibitor was significantly enhanced when tested compound was combined with HBO. What’s more, under the influence of hyperbaric oxygen, TDB significantly reduced the viability of tumor cells already at a concentration of 25 μM after 24 hours. CONCLUSIONS Hyperbaric oxygen administration significantly reduces the viability of T98G line cells and increases their sensitivity to the tested CK2 kinase inhibitor. The beneficial cytotoxic effect of TDB/HBO can be obtained at lower concentrations of the tested compound and after shorter exposure time as compared to its administration without HBO. Acknowledgement: The research was supported by the Foundation for the Development of Diagnostic and Therapy, Warsaw

Objectives The aim of this study was to investigate the pharmacokinetics, tissue distribution and anti-tumour effect of hydroxycamptothecin submicron emulsions (HCPT-SEs). Methods HCPT-SEs or HCPT injection (HCPT-I) was administered intravenously into the tail vein of rats or S180 tumour-bearing mice. Key findings HCPT-SEs increased the plasma concentration of HCPT compared with HCPT-I at all time points. The AUC0-∞, elimination half-life and mean residence time of anionic submicron emulsions containing HCPT (HCPT-ASEs) and cationic submicron emulsions containing HCPT (HCPT-CSEs) were significantly greater than those of HCPT-I (P < 0.01). Especially, a prolonged elimination half-life was found for HCPT-CSEs. HCPT-CSEs and HCPT-ASEs resulted in a 7.9-fold and 3.1-fold increase in AUC0-6h of tumour compared with HCPT-I, respectively. The targeting efficiency (Te) of HCPT-ASEs and HCPT-CSEs indicated their selectivity to tumour and the Te of HCPT-CSEs was significantly higher than that of HCPT-ASEs (P < 0.01). The anti-tumour effect studies showed that HCPT-SEs improved the therapeutic efficiency of HCPT compared with HCPT-I. The percentage of tumour growth suppression rate of mice treated with HCPT-CSEs (2.0 mg HCPT eq./kg) increased 2.1 fold compared with that of HCPT-I. Conclusions Submicron emulsions can alter the pharmacokinetic characteristics and tissue distribution of HCPT, and enhance tumour targeting and anti-tumour activity.

OLIG2 is a protein transcription factor that is expressed exclusively in progenitor cells in the brain and spinal cord during development. Typically, OLIG2 is not active in the adult brain and is not found outside the central nervous system; however, it is re-expressed in most patients with high-grade glioma (HGG). The expression of OLIG2 potentially drives the growth, invasiveness, and resistance to radiation of HGG cells and tumours in animal models. CT-179 is a small molecule (M.W. 397) that, on the basis of homology modelling studies, is a putative disruptor of OLIG2 homodimerization. We found that, at low nanomolar concentrations, CT-179 profoundly inhibited the growth of, and induced apoptosis in, a range of patient-derived HGG cell lines. Approximately half of the HGG cell lines showed substantial degradation of OLIG2 protein, and this was associated with arrest of the cells in the G2/M phase of the cell cycle. We are currently exploring whether this leads to mitotic catastrophe. Additionally, CT-179 caused significant downregulation of receptor tyrosine kinases that are associated with HGG tumorigenicity, including epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR). Orally administered CT-179 (20 mg/kg) crossed the blood-brain barrier of intact mice and reached levels sufficient to inhibit HGG cells. Indeed, the growth of established orthotopic HGG xenografts in mice was significantly inhibited by orally or intraperitoneally administered CT-179, leading to increased survival. CT-179 is one of the few small molecules that has been identified to directly inhibit the function of a transcription factor. Our experiments showing the profound anti-tumour activity of CT-179 in HGG models provide the impetus needed for moving this molecule into the clinic as a novel therapy for patients with HGG.

OLIG2 is a protein transcription factor (TF) expressed exclusively in progenitor cells in the brain and spinal cord during development and is re-expressed in most high-grade glioma (HGG) patients. Expression of OLIG2 drives the growth, invasiveness, and resistance to radiation of HGG cells and tumors in animal models. CT-179 is a novel small molecule (M.W. 397) that is a disruptor of OLIG2 homodimerization. We now show that CT-179 profoundly inhibited the growth, and induced apoptosis, in a range of patient-derived HGG cell lines at low nM concentrations. Treated cells showed substantial degradation of OLIG2 protein that was associated with G2/M arrest and mitotic catastrophe. CT-179 also caused significant down-regulation of receptor tyrosine kinases associated with HGG tumorigenicity, including EGFR and PDGFR. Orally administered CT-179 (20 mg/kg) crossed the blood-brain-barrier of intact mice reaching levels sufficient to inhibit HGG cells. Indeed, the growth of established orthotopic HGG xenografts in mice was significantly inhibited by CT-179. Our studies have provided the impetuses for moving CT-179 into the clinic as a novel therapy for patients with HGG.

Fifty-six patients with gastrointestinal cancers and four patients with benign colorectal tumours have been injected with radiolabelled anti-tumour monoclonal antibody (791T/36) to assess the degree of localization of the antibody by external scintiscanning and measurements on resected specimens. Twenty-nine patients with primary colorectal cancer showed increased uptake of the radiolabelled antibody in the resected tumours, with a tumour to normal tissue (T:NT) ratio of 2·5:1. All but two of fifteen patients with recurrent or metastatic tumour showed positive images of the deposits on external scintiscanning. Twelve patients with noncolonic gastrointestinal malignancy were studied and in only two patients were tumours demonstrated by external scanning. There were no positive images in four patients with benign colonic disease nor could increased uptake of radiolabelled antibody be demonstrated in the resected specimens. Immunohistology and autoradiography have shown that the antibody can be demonstrated in the pseudoacini and stroma of colon cancer. There are indications that this may represent localization to a cell surface antigen which becomes detached in the processing of the histological sections. It seems that in the gastrointestinal tract the monoclonal antibody 791T/36 is consistently taken up by colorectal cancer. Only a few noncolonic cancers and no benign colonic tumours take up the antibody. This antibody uptake may prove of value in the detection of occult metastases and in the targeting of antitumour agents.