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Cancer stem cells (CSCs) play a key role in non-small cell lung cancer (NSCLC) chemoresistance and metastasis. In this study, we used two NSCLC cell lines to investigate the regulating effect of hypoxia in the induction and maintenance of CSC traits. Our study demonstrated hypoxia-induced stemness and chemoresistance at levels comparable to those in typical CSC sphere culture. Activation of the NF-κB pathway (by transfection of NF-κB-p65) plays a key role in NSCLC CSCs and chemoresistance. Disulfiram (DS), an anti-alcoholism drug, showed a strong in vitro anti-CSC effect. It blocked cancer cell sphere reformation and clonogenicity, synergistically enhanced the cytotoxicity of four anti-NSCLC drugs (doxorubicin, gemcitabine, oxaliplatin and paclitaxel) and reversed hypoxia-induced resistance. The effect of DS on CSCs is copper-dependent. A very short half-life in the bloodstream is the major limitation for the translation of DS into a cancer treatment. Our team previously developed a poly lactic-co-glycolic acid (PLGA) nanoparticle encapsulated DS (DS-PLGA) with a long half-life in the bloodstream. Intra venous injection of DS-PLGA in combination with the oral application of copper gluconate has strong anticancer efficacy in a metastatic NSCLC mouse model. Further study may be able to translate DS-PLGA into cancer applications.

Abstract Angiogenesis is a multi-factorial physiological process deregulated in human diseases characterised by excessive or insufficient blood vessel formation. Emerging evidence highlights a novel role for microRNAs as regulators of angiogenesis. Previous studies addressing the effect of miR-133a expression in endothelial cells during blood vessel formation have reported conflicting results. Here, we have assessed the specific effect of mature miR-133a strands in angiogenesis and the expression of endothelial angiogenic genes. Transfection of miR-133a-3p or -5p mimics in primary human endothelial cells significantly inhibited proliferation, migration, and tubular morphogenesis of transfected cells. Screening of gene arrays related to angiogenic processes, and further validation by TaqMan qPCR, revealed that aberrant expression of miR-133a-3p led to a decrease in the expression of genes encoding pro-angiogenic molecules, whilst increasing those with anti-angiogenic functions. Ingenuity Pathway Analysis of a collection of genes differentially expressed in cells harbouring miR-133a-3p, predicted decreased cellular functions related to vasculature branching and cell cycle progression, underlining the inhibitory role of miR-133a-3p in angiogenic cellular processes. Our results suggest that controlled delivery of miR-133a-3p mimics, or antagomirs in diseased endothelial cells, might open new therapeutic interventions to treat patients suffering from cardiovascular pathologies that occur with excessive or insufficient angiogenesis.

In vitro transcribed, modified messenger RNAs (IVTmRNAs) have been used to vaccinate billions of individuals against the SARS-CoV-2 virus, and are currently being developed for many additional therapeutic applications. IVTmRNAs must be translated into proteins with therapeutic activity by the same cellular machinery that also translates native endogenous transcripts. However, different genesis pathways and routes of entry into target cells as well as the presence of modified nucleotides mean that the way in which IVTmRNAs engage with the translational machinery, and the efficiency with which they are being translated, differs from native mRNAs. This review summarises our current knowledge of commonalities and differences in translation between IVTmRNAs and cellular mRNAs, which is key for the development of future design strategies that can generate IVTmRNAs with improved activity in therapeutic applications.

Calcium signalling downstream of VEGF is essential for VEGF-induced angiogenesis. Here Savage et al. show that Transmembrane Protein 33 (TMEM33) is required for angiogenesis and the endothelial calcium response to VEGF, revealing a function for TMEM33 in multicellular organisms.

In recent years, there has been an increasing interest in oncolytic adenoviral vectors as an alternative anticancer therapy. The induction of an immune response can be considered as a major limitation of this kind of application. Significant research efforts have been focused on the development of biodegradable polymer poly-gamma-glutamic acid (γ-PGA)-based nanoparticles used as a vector for effective and safe anticancer therapy, owing to their controlled and sustained-release properties, low toxicity, as well as biocompatibility with tissue and cells. This study aimed to introduce a specific destructive and antibody blind polymer-coated viral vector into cancer cells using γ-PGA and chitosan (CH). Adenovirus was successfully encapsulated into the biopolymer particles with an encapsulation efficiency of 92% and particle size of 485 nm using the ionic gelation method. Therapeutic agents or nanoparticles (NPs) that carry therapeutics can be directed specifically to cancerous cells by decorating their surfaces using targeting ligands. Moreover, in vitro neutralizing antibody response against viral capsid proteins can be somewhat reduced by encapsulating adenovirus into γ-PGA-CH NPs, as only 3.1% of the encapsulated adenovirus was detected by anti-adenovirus antibodies in the presented work compared to naked adenoviruses. The results obtained and the unique characteristics of the polymer established in this research could provide a reference for the coating and controlled release of viral vectors used in anticancer therapy.