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Paul A Foster and Jonathan Wolf Mueller

Sulfation and desulfation pathways represent highly dynamic ways of shuttling, repressing and re-activating steroid hormones, thus controlling their immense biological potency at the very heart of endocrinology. This theme currently experiences growing research interest from various sides, including, but not limited to, novel insights about phospho-adenosine-5′-phosphosulfate synthase and sulfotransferase function and regulation, novel analytics for steroid conjugate detection and quantification. Within this review, we will also define how sulfation pathways are ripe for drug development strategies, which have translational potential to treat a number of conditions, including chronic inflammatory diseases and steroid-dependent cancers.

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Marta Correia-da-Silva, Verónica Rocha, Cláudia Marques, Cláudia M Deus, Adriana Marques-Carvalho, Paulo J Oliveira, Andreia Palmeira, Madalena Pinto, Emília Sousa, José Manuel Sousa Lobo, and Isabel Filipa Almeida

Resveratrol (RSV) is a polyphenolic compound with antioxidant, anti-inflammatory and anti-aging properties partly associated with sirtuin 1 (SIRT1)-activation in the skin. However, poor water solubility may limit RSV efficacy. This work aimed to clarify the interest of a new synthetic water-soluble RSV derivative (resveratrol glucoside sulfate, RSV-GS) for topical application. Resveratrol glucoside sulfate was synthesized using microwave-assisted sulfation. Cytotoxicity assays were performed with the keratinocyte HaCaT cell line, using MTT reduction, neutral red uptake, Alamar Blue/resazurin reduction, trypan blue exclusion and measurement of ATP concentration. Western blotting was used to evaluate SIRT1 protein content. Regarding SIRT1 binding, an in silico docking study was performed, using AutoDock Vina. Our results showed that the synthetic derivative RSV-GS was 1000 times more soluble in water than RSV and its non-sulfated glucoside. No relevant decrease in HaCaT cell viability was observed for concentrations up to 5 mM for RSV-GS, and up to 500 μM for resveratrol glucoside, while a significant decrease in HaCaT viability occurred from 100 μM for RSV. RSV-GS and RSV showed a similar behavior regarding protective effect against oxidative stress-induced cytotoxicity. SIRT1 protein content increased after treatment with 500 μM of RSV-GS and 100 μM of RSV. Moreover, in silico studies predicted that RSV-GS binds more stably to SIRT1 with a lower binding free energy than RSV. Although these results support the possible use of RSV-GS in topical formulations, in vivo safety and efficacy studies are needed before considering the use of RSV-GS in commercial products.

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Francisca Carvalhal, Marta Correia-da-Silva, Emília Sousa, Madalena Pinto, and Anake Kijjoa

Marine environment is rich in structurally unique molecules and can be an inspiring source of novel drugs. Currently, six marine-derived drugs are in the market with FDA approval and several more are in the clinical pipeline. Structurally diverse and complex secondary metabolites have been isolated from the marine world and these include sulfated steroids. Biological activities of nearly 150 marine sulfated steroids reported from 1978 to 2017 are compiled and described, namely antimicrobial, antitumor, cardiovascular and antifouling activities. Structure–activity relationship for each activity is discussed.

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Barry V L Potter

Steroid sulphatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalysing oestrogen sulphate hydrolysis to oestrogen. Drug discovery, developing the core aryl O-sulphamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women’s health. Steroidal oestrogen sulphamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral oestradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulphatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulphatase. To date, the non-steroidal sulphatase inhibitor Irosustat has been evaluated clinically in breast cancer, alone and in combination, in endometrial cancer and in prostate cancer. The versatile core pharmacophore both imbues attractive pharmaceutical properties and functions via three distinct mechanisms of action, as a pro-drug, an enzyme active-site-modifying motif, likely through direct sulphamoyl group transfer, and as a structural component augmenting activity, for example by enhancing interactions at the colchicine binding site of tubulin. Preliminary new structural data on the Pseudomonas aeruginosa arylsulphatase enzyme suggest two possible sulphamate-based adducts with the active site formylglycine as candidates for the inhibition end product via sulphamoyl or sulphonylamine transfer, and a speculative choice is suggested. The clinical status of sulphatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulphamates and non-steroidal derivatives as multi-targeting agents for hormone-independent tumours, with other emerging directions.

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William Davies

Steroid hormones can exist in functionally dissociable sulfated and non-sulfated (free) forms and can exert profound effects on numerous aspects of mammalian physiology; the ratio of free-to-sulfated steroids is governed by the antagonistic actions of steroid sulfatase (STS) and sulfotransferase (SULT) enzymes. Here, I examine evidence from human and animal model studies, which suggests that STS and its major substrate (dehydroepiandrosterone sulfate, DHEAS) and product (DHEA) can influence brain function, behaviour and mental health, before summarising how the activity of this axis varies throughout mammalian pregnancy and the postpartum period. I then consider how the steroid sulfate axis might impact upon normal maternal behaviour and how its dysfunction might contribute towards risk of postpartum psychiatric illness. Understanding the biological substrates underlying normal and abnormal maternal behaviour will be important for maximising the wellbeing of new mothers and their offspring.

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Douglas Yee

Early preclinical and population data suggested a role for the type I insulin-like growth factor receptor (IGF1R) in the regulation of breast cancer growth and survival. To target this pathway, multiple monoclonal antibodies and tyrosine kinase inhibitors were developed and tested in clinical trials. While some of the early clinical trials suggested a benefit for these drugs, none of the attempts showed improved outcomes when compared to conventional therapy. This failure of the IGF1R inhibitors was pronounced in breast cancer; multiple trials testing IGF1R inhibition in estrogen receptor-positive breast cancer were conducted, none showed benefit. This review will evaluate the rationale for IGF1R inhibition, discuss results of the clinical trials and suggest a path forward.

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L A Bach

Insulin-like growth factor-binding proteins (IGFBPs) 1–6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions. However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellular space, (ii) interaction with and modulation of other growth factor pathways including EGF, TGF-β and VEGF, and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF-independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities.

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Caterina Mancarella and Katia Scotlandi

The insulin-like growth factor (IGF) system has gained substantial interest due to its involvement in regulating cell proliferation, differentiation and survival during anoikis and after conventional and targeted therapies. However, results from clinical trials have been largely disappointing, with only a few but notable exceptions, such as trials targeting sarcomas, especially Ewing sarcoma. This review highlights key studies focusing on IGF signaling in sarcomas, specifically studies underscoring the properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. This review discusses the potential roles of IGF2 mRNA-binding proteins (IGF2BPs), discoidin domain receptors (DDRs) and metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) in regulating the IGF system. Deeper investigation of these novel regulators of the IGF system may help us to further elucidate the spatial and temporal control of the IGF axis, as understanding the control of this axis is essential for future clinical studies.

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Michelle Mohyi and Terry J Smith

Thyroid-associated ophthalmopathy (TAO) is a vexing and poorly understood autoimmune process involving the upper face and tissues surrounding the eyes. In TAO, the orbit can become inflamed and undergo substantial remodeling that is disfiguring and can lead to loss of vision. There are currently no approved medical therapies for TAO, the consequence of its uncertain pathogenic nature. It usually presents as a component of the syndrome known as Graves’ disease where loss of immune tolerance to the thyrotropin receptor (TSHR) results in the generation of activating antibodies against that protein and hyperthyroidism. The role for TSHR and these antibodies in the development of TAO is considerably less well established. We have reported over the past 2 decades evidence that the insulin-like growth factorI receptor (IGF1R) may also participate in the pathogenesis of TAO. Activating antibodies against IGF1R have been detected in patients with GD. The actions of these antibodies initiate signaling in orbital fibroblasts from patients with the disease. Further, we have identified a functional and physical interaction between TSHR and IGF1R. Importantly, it appears that signaling initiated from either receptor can be attenuated by inhibiting the activity of IGF1R. These findings underpin the rationale for therapeutically targeting IGF1R in active TAO. A recently completed therapeutic trial of teprotumumab, a human IGF1R inhibiting antibody, in patients with moderate to severe, active TAO, indicates the potential effectiveness and safety of the drug. It is possible that other autoimmune diseases might also benefit from this treatment strategy.

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Fumihiko Hakuno and Shin-Ichiro Takahashi

Insulin-like growth factors (IGFs) bind specifically to the IGF1 receptor on the cell surface of targeted tissues. Ligand binding to the α subunit of the receptor leads to a conformational change in the β subunit, resulting in the activation of receptor tyrosine kinase activity. Activated receptor phosphorylates several substrates, including insulin receptor substrates (IRSs) and Src homology collagen (SHC). Phosphotyrosine residues in these substrates are recognized by certain Src homology 2 (SH2) domain-containing signaling molecules. These include, for example, an 85 kDa regulatory subunit (p85) of phosphatidylinositol 3-kinase (PI 3-kinase), growth factor receptor-bound 2 (GRB2) and SH2-containing protein tyrosine phosphatase 2 (SHP2/Syp). These bindings lead to the activation of downstream signaling pathways, PI 3-kinase pathway and Ras-mitogen-activated protein kinase (MAP kinase) pathway. Activation of these signaling pathways is known to be required for the induction of various bioactivities of IGFs, including cell proliferation, cell differentiation and cell survival. In this review, the well-established IGF1 receptor signaling pathways required for the induction of various bioactivities of IGFs are introduced. In addition, we will discuss how IGF signals are modulated by the other extracellular stimuli or by themselves based on our studies.