The identification of a natural compound with selectively differential radiomodulating activity would arguably represent a valuable asset in the striving quest for widening the therapeutic window in ...cancer radiotherapy (RT). To this end, we fully characterized the chemical profile of olive tree leaf polyphenols from the Caiazzana cultivar (OLC), autochthonous to the Campania region (Italy), by ultra-high-performance liquid chromatography–high-resolution mass spectrometry (UHPLC-HR-MS). Oleacein was the most abundant molecule in the OLC. Two normal and two cancer cells lines were X-ray-irradiated following 24-h treatment with the same concentration of the obtained crude extract and were assessed for their radioresponse in terms of micronucleus (MN) induction and, for one of the normal cell lines, of premature senescence (PS). Irradiation of pre-treated normal cells in the presence of the OLC reduced the frequency of radiation-induced MN and the onset of PS. Conversely, the genotoxic action of ionising radiation was exacerbated in cancer cells under the same experimental conditions. To our knowledge, this is the first report on the dual action of a polyphenol-rich olive leaf extract on radiation-induced damage. If further confirmed, these findings may be pre-clinically relevant and point to a substance that may potentially counteract cancer radioresistance while reducing RT-associated normal tissue toxicity.
Exosomes are nanovesicles secreted by tumour cells which have roles in paracrine signalling during tumour progression, including tumour-stromal interactions, activation of proliferative pathways and ...bestowing immunosuppression. Hypoxia is an important feature of solid tumours which promotes tumour progression, angiogenesis and metastasis, potentially through exosome-mediated signalling.
Breast cancer cell lines were cultured under either moderate (1% O2) or severe (0.1% O2) hypoxia. Exosomes were isolated from conditioned media and quantitated by nanoparticle tracking analysis (NTA) and immunoblotting for the exosomal protein CD63 in order to assess the impact of hypoxia on exosome release. Hypoxic exosome fractions were assayed for miR-210 by real-time reverse transcription polymerase chain reaction and normalised to exogenous and endogenous control genes. Statistical significance was determined using the Student T test with a P value of < 0.05 considered significant.
Exposure of three different breast cancer cell lines to moderate (1% O2) and severe (0.1% O2) hypoxia resulted in significant increases in the number of exosomes present in the conditioned media as determined by NTA and CD63 immunoblotting. Activation of hypoxic signalling by dimethyloxalylglycine, a hypoxia-inducible factor (HIF) hydroxylase inhibitor, resulted in significant increase in exosome release. Transfection of cells with HIF-1α siRNA prior to hypoxic exposure prevented the enhancement of exosome release by hypoxia. The hypoxically regulated miR-210 was identified to be present at elevated levels in hypoxic exosome fractions.
These data provide evidence that hypoxia promotes the release of exosomes by breast cancer cells, and that this hypoxic response may be mediated by HIF-1α. Given an emerging role for tumour cell-derived exosomes in tumour progression, this has significant implications for understanding the hypoxic tumour phenotype, whereby hypoxic cancer cells may release more exosomes into their microenvironment to promote their own survival and invasion.
Phytochemical analysis of the methanolic extracts of Jatropha podagrica stalks and roots using liquid chromatography-mass spectrometry (LC-MS) led to the isolation of six compounds: corchoionoside C ...(1), isobiflorin (2), fraxin (3), hovetrichoside C (4), fraxetin (5), and corillagin (6). The isolated compounds (1–6) were tested for their cytotoxicity against MDA-MB-231 human breast cancer cells. Remarkably, compound 4 (hovetrichoside C) exhibited robust cytotoxicity against MDA-MB-231 cells, displaying an IC50 value of 50.26 ± 1.22 μM, along with an apoptotic cell death rate of 24.21 ± 2.08% at 100 μM. Treatment involving compound 4 amplified protein levels of cleaved caspase-8, -9, -3, -7, BH3-interacting domain death agonist (Bid), Bcl-2-associated X protein (Bax), and cleaved poly (ADP-ribose) polymerase (cleaved PARP), while concurrently reducing B-cell lymphoma 2 (Bcl-2) levels. In totality, these findings underscore that hovetrichoside C (4) possesses anti-breast cancer activity that revolves around apoptosis induction via both extrinsic and intrinsic signaling pathways.
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•Phytochemical analysis of Jatropha podagrica led to the isolation of six compounds (1–6).•Among the isolates, hovetrichoside C (4) exhibited robust cytotoxicity against MDA-MB-231 cells.•The cytotoxicity of compound 4 against MDA-MB-231 cells was associated with its ability to initiate apoptotic cell death.•Compound 4 amplified protein levels of cleaved caspase-8, -9, -3, -7, Bid, Bax, and cleaved PARP.•Compound 4 reduced Bcl-2 levels.
With recent approvals for multiple therapeutic antibodies that block cytotoxic T lymphocyte associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) in melanoma, non-small-cell lung ...cancer and kidney cancer, and additional immune checkpoints being targeted clinically, many questions still remain regarding the optimal use of drugs that block these checkpoint pathways. Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate, highlighted by recent approvals for two PDL1 diagnostic tests. Here, we discuss biomarkers for anti-PD1 therapy based on immunological, genetic and virological criteria. The unique biology of the CTLA4 immune checkpoint, compared with PD1, requires a different approach to biomarker development. Mechanism-based insights from such studies may guide the design of synergistic treatment combinations based on immune checkpoint blockade.
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•A series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared.•Honokiol derivative 3k exhibited the best anti-proliferative activity against HCT116 cells.•3k ...can arrest HCT116 cells in G1 phase and induce HCT116 cell death.•3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway.
Honokiol, derived from Magnolia officinalis (a traditional Chinese medicine), has been reported to have anticancer activity. Here, a series of novel honokiol thioethers bearing a 1,3,4-oxadiazole moiety were prepared and evaluated for their anticancer activities against three types of digestive system tumor cells. Biological evaluation showed that honokiol derivative 3k exhibited the best antiproliferative activity against HCT116 cells with an IC50 value of 6.1 μmol/L, superior to the reference drug 5-fluorouracil (IC50: 9.63 ± 0.27 µmol/L). The structure–activity relationships (SARs) indicated that the introduction of –(4-NO2)Ph, 3-pyridyl, –(2-F)Ph, –(4-F)Ph, –(3-F)Ph, –(4-Cl)Ph, and –(3-Cl)Ph groups was favorable for enhancing the anticancer activity of the title honokiol thioethers. Further study revealed that honokiol thioether 3k can well inhibit the proliferation of colon cancer cells HCT116, arresting the cells in G1 phase and inducing cell death. Moreover, a preliminary mechanism study indicated that 3k directly inhibits the transcription and expression of YAP protein without activating the Hippo signaling pathway. Thus, honokiol thioether 3k could be deeply developed for the development of honokiol-based anticancer candidates.
Metabolomics, which is the profiling of metabolites in biofluids, cells and tissues, is routinely applied as a tool for biomarker discovery. Owing to innovative developments in informatics and ...analytical technologies, and the integration of orthogonal biological approaches, it is now possible to expand metabolomic analyses to understand the systems-level effects of metabolites. Moreover, because of the inherent sensitivity of metabolomics, subtle alterations in biological pathways can be detected to provide insight into the mechanisms that underlie various physiological conditions and aberrant processes, including diseases.
The objective of this study was to optimise the millet formulation using Levilactobacillus brevis and to evaluate its anticarcinogenic potential in vitro. The formula was developed in the course of ...the fermentation of finger millet (Eleusine coracana) using L. brevis MTTC 4460 and optimised by response surface methodology and validation by artificial neural networking (ANN). The optimised millet formulation could be obtained using 2 % of bacterial inoculum, 2 % of glucose, and a fermentation duration of 3.3 days with a yield of 5.98 mg/mL lactic acid and 3.38 log10 (CFU/mL) viable L. brevis with overall desirability value of 1. The fermented millet formulation exhibited antiproliferative and antimigratory effects on MDA-MB-231 and HCT116 cancer cell lines. In addition, the outcomes observed in western blot analysis revealed that the formulation elicited apoptotic responses mediated by the Bcl-2 family of proteins in MDA-MB-231 and HCT116 cell lines while demonstrating no discernible impact on HEK293 normal cells.
Colorectal cancer (CRC) cell lines are widely used pre-clinical model systems. Comprehensive insights into their molecular characteristics may improve model selection for biomedical studies.
We have ...performed DNA, RNA and protein profiling of 34 cell lines, including (i) targeted deep sequencing (n = 612 genes) to detect single nucleotide variants and insertions/deletions; (ii) high resolution DNA copy number profiling; (iii) gene expression profiling at exon resolution; (iv) small RNA expression profiling by deep sequencing; and (v) protein expression analysis (n = 297 proteins) by reverse phase protein microarrays.
The cell lines were stratified according to the key molecular subtypes of CRC and data were integrated at two or more levels by computational analyses. We confirm that the frequencies and patterns of DNA aberrations are associated with genomic instability phenotypes and that the cell lines recapitulate the genomic profiles of primary carcinomas. Intrinsic expression subgroups are distinct from genomic subtypes, but consistent at the gene-, microRNA- and protein-level and dominated by two distinct clusters; colon-like cell lines characterized by expression of gastro-intestinal differentiation markers and undifferentiated cell lines showing upregulation of epithelial-mesenchymal transition and TGFβ signatures. This sample split was concordant with the gene expression-based consensus molecular subtypes of primary tumors. Approximately ¼ of the genes had consistent regulation at the DNA copy number and gene expression level, while expression of gene-protein pairs in general was strongly correlated. Consistent high-level DNA copy number amplification and outlier gene- and protein- expression was found for several oncogenes in individual cell lines, including MYC and ERBB2.
This study expands the view of CRC cell lines as accurate molecular models of primary carcinomas, and we present integrated multi-level molecular data of 34 widely used cell lines in easily accessible formats, providing a resource for preclinical studies in CRC.
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