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Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways. A new study in PLOS Biology demonstrates that combined therapy targeting enhancer of zeste homolog 2 (EZH2) and histone deacetylases (HDACs) may sensitize CRPC to both epigenetic and standard therapies.

With several gold nanoparticle-based therapies currently undergoing clinical trials, these treatments may soon be in the clinic as novel anticancer agents. Gold nanoparticles are the subject of a wide ranging international research effort with preclinical studies underway for multiple applications including photoablation, diagnostic imaging, radiosensitization and multifunctional drug-delivery vehicles. These applications require an increasingly complex level of surface modification in order to achieve efficacy and limit off-target toxicity. This review will discuss the main obstacles in relation to surface functionalization and the chemical approaches commonly utilized. Finally, we review a range of recent preclinical studies that aim to advance gold nanoparticle treatments toward the clinic.

The common liver fluke ( Fasciola hepatica ) causes the disease fasciolosis, which results in considerable losses within the global agri-food industry. There is a shortfall in the drugs that are effective against both the adult and juvenile life stages within the mammalian host, such that new drug targets are needed. Over the last decade the stem cells of parasitic flatworms have emerged as reservoirs of putative novel targets due to their role in development and homeostasis, including at host-parasite interfaces. Here, we investigate and characterise the proliferating cells that underpin development in F . hepatica . We provide evidence that these cells are capable of self-renewal, differentiation, and are sensitive to ionising radiation— all attributes of neoblasts in other flatworms. Changes in cell proliferation were also noted during the early stages of in vitro juvenile growth/development (around four to seven days post excystment), which coincided with a marked reduction in the nuclear area of proliferating cells. Furthermore, we generated transcriptomes from worms following irradiation-based ablation of neoblasts, identifying 124 significantly downregulated transcripts, including known stem cell markers such as fgfrA and plk1 . Sixty-eight of these had homologues associated with neoblast-like cells in Schistosoma mansoni . Finally, RNA interference mediated knockdown of histone h2b (a marker of proliferating cells), ablated neoblast-like cells and impaired worm development in vitro . In summary, this work demonstrates that the proliferating cells of F . hepatica are equivalent to neoblasts of other flatworm species and demonstrate that they may serve as attractive targets for novel anthelmintics.

DNA methylation is a reversible process catalyzed by the ten–eleven translocation (TET) family of enzymes (TET1, TET2, TET3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis. Understanding the mechanisms leading to 5hmC loss and its role in oncogenesis will advance the development of epigenetic-based therapeutics. We show that TET2 loss associates with glioblastoma (GBM) stem cells and correlates with poor survival of GBM patients. We further identify a SOX2:miR-10b-5p:TET2 axis that represses TET2 expression, represses 5hmC, increases 5mC levels, and induces GBM cell stemness and tumor-propagating potential. In vivo delivery of a miR-10b-5p inhibitor that normalizes TET2 expression and 5hmC levels inhibits tumor growth and prolongs survival of animals bearing pre-established orthotopic GBM xenografts. These findings highlight the importance of TET2 and 5hmC loss in Sox2-driven oncogenesis and their potential for therapeutic targeting.

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non–neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

Most human cancers are aneuploid and have chromosomal instability, which contrasts to the inability of human cells to normally tolerate aneuploidy. Noting that aneuploidy in human breast cancer correlates with increased expression levels of the Mps1 checkpoint gene, we investigated whether these high levels of Mps1 contribute to the ability of breast cancer cells to tolerate this aneuploidy. Reducing Mps1 levels in cultured human breast cancer cells by RNAi resulted in aberrant mitoses, induction of apoptosis, and decreased ability of human breast cancer cells to grow as xenografts in nude mice. Remarkably, breast cancer cells that survive reductions in levels of Mps1 have relatively less aneuploidy, as measured by copies of specific chromosomes, compared with cells that have constitutively high levels of Mps1. Thus, high levels of Mps1 in breast cancer cells likely contribute to these cells tolerating aneuploidy.

Vat photopolymerisation (VP) three-dimensional printing (3DP) has attracted great attention in many different fields, such as electronics, pharmaceuticals, biomedical devices and tissue engineering. Due to the low availability of biocompatible photocurable resins, its application in the healthcare sector is still limited. In this work, we formulate photocurable resins based on urethane dimethacrylate (UDMA) combined with three different difunctional methacrylic diluents named ethylene glycol dimethacrylate (EGDMA), di(ethylene glycol) dimethacrylate (DEGDMA) or tri(ethylene glycol) dimethacrylate (TEGDMA). The resins were tested for viscosity, thermal behaviour and printability. After printing, the 3D printed specimens were measured with a digital calliper in order to investigate their accuracy to the digital model and tested with FT-IR, TGA and DSC. Their mechanical properties, contact angle, water sorption and biocompatibility were also evaluated. The photopolymerizable formulations investigated in this work achieved promising properties so as to be suitable for tissue engineering and other biomedical applications. Graphical abstract

This follow-up study aims to determine the physical parameters which govern the differential radiosensitization capacity of two tumor cell lines and one immortalized normal cell line to 1.9 nm gold nanoparticles. In addition to comparing the uptake potential, localization, and cytotoxicity of 1.9 nm gold nanoparticles, the current study also draws on comparisons between nanoparticle size and total nanoparticle uptake based on previously published data. We quantified gold nanoparticle uptake using atomic emission spectroscopy and imaged intracellular localization by transmission electron microscopy. Cell growth delay and clonogenic assays were used to determine cytotoxicity and radiosensitization potential, respectively. Mechanistic data were obtained by Western blot, flow cytometry, and assays for reactive oxygen species. Gold nanoparticle uptake was preferentially observed in tumor cells, resulting in an increased expression of cleaved caspase proteins and an accumulation of cells in sub G(1) phase. Despite this, gold nanoparticle cytotoxicity remained low, with immortalized normal cells exhibiting an LD(50) concentration approximately 14 times higher than tumor cells. The surviving fraction for gold nanoparticle-treated cells at 3 Gy compared with that of untreated control cells indicated a strong dependence on cell type in respect to radiosensitization potential. Gold nanoparticles were most avidly endocytosed and localized within cytoplasmic vesicles during the first 6 hours of exposure. The lack of significant cytotoxicity in the absence of radiation, and the generation of gold nanoparticle-induced reactive oxygen species provide a potential mechanism for previously reported radiosensitization at megavoltage energies.

Background Hypoxia, a key feature of most solid tumours, including head and neck cancer, reduces radiotherapy efficacy by promoting radiation resistance through micro-environmental and genomic alterations. Addressing these resistance mechanisms is crucial, as radiotherapy remains central to managing locally advanced disease. Atovaquone, a mitochondrial electron transport chain complex III inhibitor, is reported to reduce tumour hypoxia in preclinical models, however, this response does not consistently enhance radiation sensitivity. This work examines the potential of atovaquone to modify the hypoxic response in models of head and neck squamous cell carcinoma (HNSCC), uncovering an adaptive resistance mechanism driven by integrated stress response (ISR) signaling that limits the radiosensitising potential of this approach. Methods The bioenergetic response of HNSCC cells to atovaquone was assessed using the Seahorse XFe96 Analyzer with the XF Cell Mito Stress Test. Radiation dose modifying effects of atovaquone were tested by clonogenic survival assays, while ROS yields were analysed by flow cytometry. Western blotting and quantitative reverse transcription-PCR were employed to study activation of ISR signaling and the overall influence of atovaquone on the hypoxic response. Finally, the role of the ISR activation in modulating radiosensitivity was investigated using both siRNA and pharmacological inhibition of eIF2α, a central regulator of the ISR. Results Herein we report that atovaquone significantly disrupts mitochondrial respiration, triggering phosphorylation of eIF2α, a pivotal regulator of the ISR, and a master regulator of protein synthesis. Notably, atovaquone also increased the autophagic load under hypoxia, while autophagy inhibition significantly enhanced apoptosis, improving radiation sensitivity. Combined eIF2α inhibition and atovaquone promotes cell cycle redistribution and significantly enhances mitochondrial ROS production and compared to atovaquone alone, restoring atovaquone mediated radiosensitisation. Conclusions Our data highlight dual counter opposing impacts of atovaquone, serving as a hypoxic radiosensitiser though oxidative phosphorylation (OXPHOS) inhibition, but also in promoting stress induced ISR signaling, conferring resistance to radiation treatment. Importantly, if ISR activation is impeded, the metabolic radiosensitising properties of atovaquone is restored. These data provide a new insight to a molecular response that could help counteract hypoxia-induced radioresistance. Plain English summary Solid tumours, including head and neck cancer, have poorly oxygenated regions, termed hypoxic, making them less responsive to radiotherapy. Hypoxia not only changes the local tumour environment but also alters the genetic behaviour of the tumour, contributing to treatment resistance. Atovaquone, a drug that inhibits oxygen dependent respiration with the mitochondria, has been shown to sensitise tumour models to radiation by reducing oxygen consumption, a strategy referred to as metabolic radiosensitisation. However, this response is inconsistent between tumour models. In this study, we explored how atovaquone affects the response of head and neck cancer cells to radiation under both normoxic (21% O 2 ) and hypoxic (0.5% O 2 ) conditions. We found that while atovaquone disrupts mitochondrial energy production, it also activates a stress response pathway called the integrated stress response (ISR). This highly conserved pathway helps protect tumour cells against the metabolism altering properties of atovaquone, ultimately reducing the effectiveness of radiation. Using inhibitors (both drug and genetic) of key proteins in the integrated stress response signaling pathway, tumour cells were rendered more sensitive to radiation, enhancing cell death. These results reveal that while atovaquone has the potential to enhance radiation therapy by reducing hypoxia, it simultaneously triggers protective stress response mechanisms within the tumour cells. By targeting the ISR, we could improve the effectiveness of atovaquone and radiation therapy together. This research offers new strategies to tackle hypoxia-related treatment resistance in cancer.

Gold nanoparticles (GNPs) are being proposed as contrast agents to enhance X-ray imaging and radiotherapy, seeking to take advantage of the increased X-ray absorption of gold compared to soft tissue. However, there is a great discrepancy between physically predicted increases in X-ray energy deposition and experimentally observed increases in cell killing. In this work, we present the first calculations which take into account the structure of energy deposition in the nanoscale vicinity of GNPs and relate this to biological outcomes and show for the first time good agreement with experimentally observed cell killing by the combination of X-rays and GNPs. These results are not only relevant to radiotherapy, but also have implications for applications of heavy atom nanoparticles in biological settings or where human exposure is possible because the localised energy deposition high-lighted by these results may cause complex DNA damage, leading to mutation and carcinogenesis.