Lipophilic aroylhydrazone chelator HNTMB and its multiple effects on ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>Metal chelators have gained much attention as potential anti-cancer agents. However, the effects of chelators are often linked solely to their capacity to bind iron while the potential complexation of other trace metals has not been fully investigated. In present study, we evaluated the effects of various lipophilic aroylhydrazone chelators (AHC), including novel compound HNTMB, on various ovarian cancer cell lines (SKOV-3, OVCAR-3, NUTU-19).</p> <p>Methods</p> <p>Cell viability was analyzed via MTS cytotoxicity assays and NCI60 cancer cell growth screens. Apoptotic events were monitored via Western Blot analysis, fluorescence microscopy and TUNEL assay. FACS analysis was carried out to study Cell Cycle regulation and detection of intracellular Reactive Oxygen Species (ROS)</p> <p>Results</p> <p>HNTMB displayed high cytotoxicity (IC50 200-400 nM) compared to previously developed AHC (oVtBBH, HNtBBH, StBBH/206, HNTh2H/315, HNI/311; IC50 0.8-6 μM) or cancer drug Deferoxamine, a hexadentate iron-chelator (IC50 12-25 μM). In a NCI60 cancer cell line screen HNTMB exhibited growth inhibitory effects with remarkable differences in specificity depending on the cell line studied (GI50 10 nM-2.4 μM). In SKOV-3 ovarian cancer cells HNTMB treatment led to chromatin fragmentation and activation of the extrinsic and intrinsic pathways of apoptosis with specific down-regulation of Bcl-2. HNTMB caused delayed cell cycle progression of SKOV-3 through G2/M phase arrest. HNTMB can chelate iron and copper of different oxidation states. Complexation with copper lead to high cytotoxicity via generation of reactive oxygen species (ROS) while treatment with iron complexes of the drug caused neither cytotoxicity nor increased ROS levels.</p> <p>Conclusions</p> <p>The present report suggests that both, non-complexed HNTMB as a chelator of intracellular trace-metals as well as a cytotoxic HNTMB/copper complex may be developed as potential therapeutic drugs in the treatment of ovarian and other solid tumors.</p

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Three individuals, three stories, three burials from medieval Trondheim, Norway

This article presents the life stories of three individuals who lived in Trondheim, Norway, dur- ing the 13th century. Based on skeletal examinations, facial reconstructions, genetic analy- ses, and stable oxygen isotope analyses, the birthplace, mobility, ancestry, pathology, and physical appearance of these people are presented. The stories are discussed within the relevant historical context. These three people would have been ordinary citizens, without any privileges out of the ordinary, which makes them quite rare in the academic literature. Through the study of individuals one gets a unique look into the Norwegian medieval society

The placement of the human eyeball and canthi in craniofacial identification

An accurate understanding of the spatial relationships between the deep and superficial structures of the head is essential for anthropological methods concerned with the comparison of faces to skulls (superimposition) or the prediction of faces from them (facial approximation). However, differences of opinion exist concerning: (i) the position of the eyeball in planes other than the anteroposterior plane and (ii) the canthi positions relative to the bony orbital margins. This study attempts to clarify the above relationships by dissection of a small sample of adult human cadavers (N = 4, mean age = 83 years, s = 12 years). The most notable finding was that the eyeballs were not centrally positioned within the orbits as the more recent craniofacial identification literature expounds. Rather, the eyeballs were consistently positioned closer to the orbital roof and lateral orbital wall (by 1-2 mm on average); a finding consistent with the earlier anatomical literature. While these estimation errors are small ipsilaterally, several factors make them meaningful: (i) the orbital region is heavily used for facial recognition; (ii) the width error is doubled because the eyes are bilateral structures; (iii) the eyes are sometimes used to predict/assess other soft tissue facial structures; and (iv) the net error in facial approximation rapidly accumulates with the subsequent prediction of each independent facial feature. While the small sample size of this study limits conclusive generalizations, the new data presented here nonetheless have immediate application to craniofacial identification practice because the results are evidence based. In contrast, metric data have never been published to support the use of the central positioning guideline. Clearly, this study warrants further quantification of the eyeball position in larger samples and preferably of younger individuals