Arsenoplatins are adducts of two chemically important anticancer drugs, cisplatin and arsenic trioxide, that have a Pt(II) bond to an As(III) hydroxide center. Screens of the NCI-60 human tumor ...cell lines reveal that arsenoplatin-1 (AP-1), Pt(μ-NHC(CH3)O)2ClAs(OH)2, the first representative of this novel class of anticancer agents, displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in a majority of cancer cell lines tested. These activity profiles are important because the success of arsenic trioxide in blood cancers (such as APL) has not been seen in solid tumors due to the rapid clearance of arsenous acid from the body. To understand the biological chemistry of these compounds, we evaluated interactions of AP-1 with the two important classes of biomoleculesproteins and DNA. The first structural studies of AP-1 bound to model proteins reveal that platinum(II) binds the Nε of His in a manner that preserves the Pt–As bond. We find that AP-1 readily enters cells and binds to DNA with an intact Pt–As bond (Pt:As ratio of 1). At longer incubation times, however, the Pt:As ratio in DNA samples increases, suggesting that the Pt–As bond breaks and releases the As(OH)2 moiety. We conclude that arsenoplatin-1 has the potential to deliver both Pt and As species to a variety of hematological and solid cancers.
Advances in cancer therapy have increased the rate of survival of young cancer patients; however, female lymphoma patients frequently face a temporary or permanent loss of fertility when treated with ...traditional cytotoxic agents. The potential loss of fertility is an important concern that can influence treatment decisions for many premenopausal cancer patients. The negative effect of chemotherapeutic agents and treatment protocols to patients' fertility-referred to as fertotoxicity-are thus an increasingly important cancer survivorship issue. We have developed a novel nanoscale formulation of arsenic trioxide, a potent drug for treatment of hematological malignancies, and demonstrate that it has significantly better activity in a murine lymphoma model than the free drug. In parallel, we have developed a novel in vitro assay of ovarian follicle function that predicts in vivo ovarian toxicity of therapeutic agents. Our results reveal that the nanotherapeutic agent is not only more active against lymphoma, but is fertoprotective, i.e., it is much less deleterious to ovarian function than the parent drug. Thus, our in vitro assay allows rapid evaluation of both established and experimental anticancer drugs on ovarian reserve and can inform the selection of efficacious and fertility-sparing treatment regimens for reproductive-age women diagnosed with cancer.
The urokinase plasminogen activator receptor (uPAR) mediates cell motility and tissue remodeling. Although uPAR may be expressed transiently in many tissues during development and wound healing, its ...constitutive expression appears to be associated with several pathological conditions, including cancer. uPAR expression has been demonstrated in most solid tumors and several hematologic malignancies including multiple myeloma and acute leukemias.Unlike many tumor antigens, uPAR is present not only in tumor cells but also in a number of tumor-associated cells including angiogenic endothelial cells and macrophages. The expression of uPAR has been shown to be fairly high in tumor compared to normal, quiescent tissues, which has led to uPAR being proposed as a therapeutic target, as well as a targeting agent, for the treatment of cancer. The majority of therapeutic approaches that have been investigated to date have focused on inhibiting the urokinase plasminogen activator (uPA)-uPAR interaction but these have not led to the development of a viable uPAR targeted clinical candidate. Genetic knockdown approaches e.g. siRNA, shRNA focused on decreasing uPAR expression have demonstrated robust antitumor activity in pre-clinical studies but have been hampered by the obstacles of stability and drug delivery that have limited the field of RNA nucleic acid based therapeutics. More recently, novel approaches that target interactions of uPAR that are downstream of uPA binding e.g. with integrins or that exploit observations describing the biology of uPAR such as mediating uPA internalization and signaling have generated novel uPAR targeted candidates that are now advancing towards clinic evaluation. This review will discuss some of the pitfalls that have delayed progress on uPAR-targeted interventions and will summarize recent progress in the development of uPAR-targeted therapeutics.
Psoriasis is an immune-mediated, inflammatory disorder of the skin characterized by chronic inflammation and hyperproliferation of the epidermis. Differential expression analysis of microarray or ...RNA-seq data have shown that thousands of coding and non-coding genes are differentially expressed between psoriatic and healthy control skin. However, differential expression analysis may fail to detect perturbations in gene coexpression networks. Sensitive detection of such networks may provide additional insight into important disease-associated pathways. In this study, we applied weighted gene coexpression network analysis (WGCNA) on RNA-seq data from psoriasis patients and healthy controls.
RNA-seq was performed on skin samples from 18 psoriasis patients (pre-treatment and post-treatment with the TNF-α inhibitor adalimumab) and 16 healthy controls, generating an average of 52.3 million 100-bp paired-end reads per sample. Using WGCNA, we identified 3 network modules that were significantly correlated with psoriasis and 6 network modules significantly correlated with biologic treatment, with only 16 % of the psoriasis-associated and 5 % of the treatment-associated coexpressed genes being identified by differential expression analysis. In a majority of these correlated modules, more than 50 % of coexpressed genes were long non-coding RNAs (lncRNA). Enrichment analysis of these correlated modules revealed that short-chain fatty acid metabolism and olfactory signaling are amongst the top pathways enriched for in modules associated with psoriasis, while regulation of leukocyte mediated cytotoxicity and regulation of cell killing are amongst the top pathways enriched for in modules associated with biologic treatment. A putative autoantigen, LL37, was coexpressed in the module most correlated with psoriasis.
This study has identified several networks of coding and non-coding genes associated with psoriasis and biologic drug treatment, including networks enriched for short-chain fatty acid metabolism and olfactory receptor activity, pathways that were not previously identified through differential expression analysis and may be dysregulated in psoriatic skin. As these networks are comprised mostly of non-coding genes, it is likely that non-coding genes play critical roles in the regulation of pathways involved in the pathogenesis of psoriasis.
Background and Aims
Sterile inflammation is a major clinical concern during ischemia‐reperfusion injury (IRI) triggered by traumatic events, including stroke, myocardial infarction, and solid organ ...transplantation. Despite high‐mobility group box 1 (HMGB1) clearly being involved in sterile inflammation, its role is controversial because of a paucity of patient‐focused research.
Approach and Results
Here, we examined the role of HMGB1 oxidation states in human IRI following liver transplantation. Portal blood immediately following allograft reperfusion (liver flush; LF) had increased total HMGB1, but only LF from patients with histopathological IRI had increased disulfide‐HMGB1 and induced Toll‐like receptor 4–dependent tumor necrosis factor alpha production by macrophages. Disulfide HMGB1 levels increased concomitantly with IRI severity. IRI+ prereperfusion biopsies contained macrophages with hyperacetylated, lysosomal disulfide‐HMGB1 that increased postreperfusion at sites of injury, paralleling increased histone acetyltransferase general transcription factor IIIC subunit 4 and decreased histone deacetylase 5 expression. Purified disulfide‐HMGB1 or IRI+ blood stimulated further production of disulfide‐HMGB1 and increased proinflammatory molecule and cytokine expression in macrophages through a positive feedback loop.
Conclusions
These data identify disulfide‐HMGB1 as a mechanistic biomarker of, and therapeutic target for, minimizing sterile inflammation during human liver IRI.
The urokinase plasminogen activator receptor (uPAR) plays a role in tumor progression and has been proposed as a target for the treatment of cancer. We recently described the development of a novel ...humanized monoclonal antibody that targets uPAR and has anti-tumor activity in multiple xenograft animal tumor models. This antibody, ATN-658, does not inhibit ligand binding (i.e. uPA and vitronectin) to uPAR and its mechanism of action remains unclear. As a first step in understanding the anti-tumor activity of ATN-658, we set out to identify the epitope on uPAR to which ATN-658 binds. Guided by comparisons between primate and human uPAR, epitope mapping studies were performed using several orthogonal techniques. Systematic site directed and alanine scanning mutagenesis identified the region of aa 268-275 of uPAR as the epitope for ATN-658. No known function has previously been attributed to this epitope Structural insights into epitope recognition were obtained from structural studies of the Fab fragment of ATN-658 bound to uPAR. The structure shows that the ATN-658 binds to the DIII domain of uPAR, close to the C-terminus of the receptor, corroborating the epitope mapping results. Intriguingly, when bound to uPAR, the complementarity determining region (CDR) regions of ATN-658 closely mimic the binding regions of the integrin CD11b (αM), a previously identified uPAR ligand thought to be involved in leukocyte rolling, migration and complement fixation with no known role in tumor progression of solid tumors. These studies reveal a new functional epitope on uPAR involved in tumor progression and demonstrate a previously unrecognized strategy for the therapeutic targeting of uPAR.
An air- and moisture-tolerant enantioselective hydrosilylation of N-phosphinyl imines employing a chiral Re(V)−oxo complex as a catalyst is described. The chiral catalyst is a cyanobis(oxazoline) ...(CNbox)-ligated rhenium−oxo complex of the general formula (CNbox)Re(O)Cl2(OPPh3). Using this catalyst, a wide range of aromatic imines (including cyclic, acyclic, and heteroaromatic), α-iminoesters, and α,β-unsaturated imines are reduced with good to excellent enantioselectivities.
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