Gliomas are highly malignant brain tumours characterised by extensive areas of poor perfusion which subsequently leads to hypoxia and reduced survival. Therapies that address the hypoxic microenvironment are likely to significantly improve patient outcomes. Verteporfin, a benzoporphyrin-like drug, has been suggested to target the Yes-associated protein (YAP). Increased YAP expression and transcriptional activity has been proposed in other tumour types to promote malignant cell survival and thus YAP-inhibitor, verteporfin, may be predicted to impact glioma cell growth and viability. Due to the extensive hypoxic nature of gliomas, we investigated the effect of hypoxia on YAP expression and found that YAP transcription is increased under these conditions. Treatment of both primary and immortalised glioblastoma cell lines with verteporfin resulted in a significant decrease in viability but strikingly only under hypoxic conditions (1% O2). We discovered that cell death occurs through a YAP-independent mechanism, predominately involving binding of free iron and likely through redox cycling, contributes to production of reactive oxygen species. This results in disruption of normal cellular processes and death in cells already under oxidative stress – such as those in hypoxia. We suggest that through repurposing verteporfin, it represents a novel means of treating highly therapy-resistant, hypoxic cells in glioma.
Deoxyribonucleic
acid (DNA) has been hypothesized to act as a molecular
wire due to the presence of an extended π-stack between base
pairs, but the factors that are detrimental in the mechanism of charge
transport (CT) across tunnel junctions with DNA are still unclear.
Here we systematically investigate CT across dense DNA monolayers
in large-area biomolecular tunnel junctions to determine when intrachain
or interchain CT dominates and under which conditions the mechanism
of CT becomes thermally activated. In our junctions, double-stranded
DNA (dsDNA) is 30-fold more conductive than single-stranded DNA (ssDNA).
The main reason for this large change in conductivity is that dsDNA
forms ordered monolayers where intrachain tunneling dominates, resulting
in high CT rates. By varying the temperature T and
the length of the DNA fragments in the junctions, which determines
the tunneling distance, we reveal a complex interplay between T, the length of DNA, and structural order on the mechanism
of charge transport. Both the increase in the tunneling distance and
the decrease in structural order result in a change in the mechanism
of CT from coherent tunneling to incoherent tunneling (hopping). Our
results highlight the importance of the interplay between structural
order, tunneling distance, and temperature on the CT mechanism across
DNA in molecular junctions.
Four new bis‐substituted ferrocene derivatives containing either a hydroxyalkyl or methoxyalkyl group and either a thyminyl or methylthyminyl group have been synthesised and characterised by a range of spectroscopic and analytical techniques. They were included in a structure‐activity‐relationship (SAR) study probing anticancer activities in osteosarcoma (bone cancer) cell lines and were compared with a known lead compound, 1‐(S,Rp), a nucleoside analogue that is highly toxic to cancer cells. Biological studies using the MTT assay revealed that a regioisomer of ferronucleoside 1‐(S,Rp), which only differs from the lead compound in being substituted on two cyclopentadienyl rings rather than one, was over 20 times less cytotoxic. On the other hand, methylated derivatives of 1‐(S,Rp) showed comparable cytotoxicities to the lead compound. Overall these studies indicate that a mechanism of action for 1‐(S,Rp) cannot proceed through alcohol phosphorylation and that its geometry and size, rather than any particular functional group, are crucial factors in explaining its high anticancer activity.
Changing the metal atom within a metallocene nucleoside analogue from iron to ruthenium results in a five-fold reduction in biological activity in a pancreatic cancer cell line.
Iron works: A ferrocene derivative, one of a series of ferronucleosides designed by the Tucker group, shows micromolar toxicity in a range of cancer cell lines. Their latest research shows the importance to activity of having arms in adjacent positions, with the 1,1’‐regioisomer much less active in bone cancer cell lines. On the other hand, N‐ or O‐methylation has much less of an effect; this rules out a conventional mechanism of action for a nucleoside, giving further weight to one that involves the iron centre. More information can be found in the full paper by N. J. Hodges, J. H. R. Tucker et al.
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