Investigating metal aberrations in cellular senescence

This study explored perturbations in iron and copper homeostasis in senescent cells that contribute to age-associated disease and dysfunction. Altered metal regulation was associated with impaired cellular autophagy and resulted in extreme resistance to ferroptosis, a novel iron mediated cell death process linked to various pathologies.<br /

Copper as a target for prostate cancer therapeutics: copper-ionophore pharmacology and altering systemic copper distribution

Copper-ionophores that elevate intracellular bioavailable copper display significant therapeutic utility against prostate cancer cells in vitro and in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice. However, the pharmacological basis for their anticancer activity remains unclear, despite impending clinical trails. Herein we show that intracellular copper levels in prostate cancer, evaluated in vitro and across disease progression in TRAMP mice, were not correlative with copper-ionophore activity and mirrored the normal levels observed in patient prostatectomy tissues (Gleason Score 7 & 9). TRAMP adenocarcinoma cells harbored markedly elevated oxidative stress and diminished glutathione (GSH)-mediated antioxidant capacity, which together conferred selective sensitivity to prooxidant ionophoric copper. Copper-ionophore treatments [CuII(gtsm), disulfiram & clioquinol] generated toxic levels of reactive oxygen species (ROS) in TRAMP adenocarcinoma cells, but not in normal mouse prostate epithelial cells (PrECs). Our results provide a basis for the pharmacological activity of copper-ionophores and suggest they are amendable for treatment of patients with prostate cancer. Additionally, recent in vitro and mouse xenograft studies have suggested an increased copper requirement by prostate cancer cells. We demonstrated that prostate adenocarcinoma development in TRAMP mice requires a functional supply of copper and is significantly impeded by altered systemic copper distribution. The presence of a mutant copper-transporting Atp7b protein (tx mutation: A4066G/Met1356Val) in TRAMP mice changed copper-integration into serum and caused a remarkable reduction in prostate cancer burden (64% reduction) and disease severity (grade), abrogating adenocarcinoma development. Implications for current clinical trials are discussed

Redox active metals in neurodegenerative diseases

Copper (Cu) and iron (Fe) are redox active metals essential for the regulation of cellular pathways that are fundamental for brain function, including neurotransmitter synthesis and release, neurotransmission, and protein turnover. Cu and Fe are tightly regulated by sophisticated homeostatic systems that tune the levels and localization of these redox active metals. The regulation of Cu and Fe necessitates their coordination to small organic molecules and metal chaperone proteins that restrict their reactions to specific protein centres, where Cu and Fe cycle between reduced (Fe2+, Cu+) and oxidised states (Fe3+, Cu2+). Perturbation of this regulation is evident in the brain affected by neurodegeneration. Here we review the evidence that links Cu and Fe dyshomeostasis to neurodegeneration as well as the promising preclinical and clinical studies reporting pharmacological intervention to remedy Cu and Fe abnormalities in the treatment of Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS)

Cellular Senescence and Iron Dyshomeostasis in Alzheimer's Disease

Iron dyshomeostasis is a feature of Alzheimer's disease (AD). The impact of iron on AD is attributed to its interactions with the central proteins of AD pathology (amyloid precursor protein and tau) and/or through the iron-mediated generation of prooxidant molecules (e.g., hydroxyl radicals). However, the source of iron accumulation in pathologically relevant regions of the brain and its contribution to AD remains unclear. One likely contributor to iron accumulation is the age-associated increase in tissue-resident senescent cells that drive inflammation and contribute to various pathologies associated with advanced age. Iron accumulation predisposes ageing tissue to oxidative stress that can lead to cellular dysfunction and to iron-dependent cell death modalities (e.g., ferroptosis). Further, elevated brain iron is associated with the progression of AD and cognitive decline. Elevated brain iron presents a feature of AD that may be modified pharmacologically to mitigate the effects of age/senescence-associated iron dyshomeostasis and improve disease outcome

Heterogeneous copper concentrations in cancerous human prostate tissues

&copy; 2015 Wiley Periodicals, Inc. &copy; 2015 Wiley Periodicals, Inc. Background Therapeutics that target copper for the treatment of prostate cancer are being evaluated in human clinical trials. Elevated intracellular copper is considered to sensitize prostate cancer cells to certain copper-coordination compounds, especially those with ionophoric properties. While there is compelling in vitro evidence that prostate cancer cells accumulate intracellular copper, a corresponding status for copper in patient tissues has not been corroborated. We therefore established whether copper concentrations increase in cancerous prostate tissues, and in sera, in patients throughout disease progression. Methods Human prostate tissue samples were obtained from patient prostatectomies (n=28), and together with patient-matched sera, were analyzed for copper content by inductively coupled plasma mass spectrometry. Results When grouped together, cancerous prostate tissues exhibiting moderate disease severity (Gleason Score 7) (n=10) had 1.6-fold more copper than age-matched normal tissues (n=10) (P&lt;0.05). Those with more aggressive disease (Gleason Score 9) (n=8) had 1.8-fold more copper (P&lt;0.05). In both disease stages however, the copper concentrations between individual samples were rather variable (0.55-3.02&mu;g/g), with many clearly within the normal range (0.52-1.28&mu;g/g). Additionally, we found that there was no change in serum copper concentrations in patients with either moderate or aggressive prostate cancer (Gleason Score 7 or 9), compared with reference intervals and to age-matched controls. Conclusions The heterogeneous nature of copper concentrations in cancerous prostate tissues, suggest that a small subset of patients may respond to treatments that target elevated intratumoral copper. Therefore, such approaches would likely require personalized treatment strategies. Prostate 75:1510-1517, 2015

Striking while the iron is hot: Iron metabolism and ferroptosis in neurodegeneration

Iron is the most abundant transition metal on Earth and essential for life. Iron availability inprimordial oceans allowed for its incorporation in living organisms. Metabolic processes catalysed byiron or by iron-sulfur clusters that could be generated in prebiotic settings may be among the first ofsuch processes to evolve on Earth and essential for the emergence of carbon-based life (Bonfio et al.,2017, Varma et al., 2018). The photolysis of water by the process of photosynthesis around 2.45billion years ago introduced a new global poison i.e. oxygen, causing what is described as the GreatOxygenation Event (Sessions et al., 2009). The resultant oxidising environment transformed iron intoa limiting factor for life processes due to the limited solubility of the oxidised iron cation.The ability of iron to cycle through its oxidation states and form coordination bonds is utilisedby many enzymes to carry out their catalytic function. Iron has thus emerged as an indispensable cofactorfor proteins involved in essential (respiration, DNA replication, cell division) and specialised(oxygen transport, neurotransmission) cellular functions. Iron can serve as a potent oxidant that canwreak havoc on biomolecules, ironically endangering the life that it helps facilitate. This conundrumnecessitated the evolution of homeostatic mechanisms to ensure the availability of this critical elementwhile mitigating potential oxidative damage. In the body iron levels are maintained through theprecise uptake of iron from the diet. However, the body has no specific physiological mechanism foriron excretion. Iron thus tends to accumulate in certain tissues with age.The brain is a major organ where iron accumulates with age, especially in regions ofpathological relevance. The study of monogenic genetic disorders that affect iron homeostasis, andindications from dietary studies, have established that brain iron homeostasis is mostly independent ofsystemic iron homeostasis (Belaidi and Bush, 2016). Furthermore, indicators of systemic iron levelsare weakly correlated with iron in the brain. Several neurodegenerative conditions includingAlzheimer's disease (AD) and Parkinson's disease (PD) are associated with increased iron levels inaffected region of the brain with levels of iron corresponding to disease severity (Belaidi and Bush,2016). However, the iron-mediated events that may promote neurodegeneration appear to be moreintricate than iron-associated oxidative damage. Here we review the development of the “iron4hypothesis” of neurodegeneration, shifting our focus beyond iron toxicity to consider the recently(re)discovered iron-dependent programmed cell death pathway called ferroptosis