Marine Compounds for Melanoma Treatment and Prevention.

Melanoma is considered a multifactorial disease etiologically divided into melanomas related to sun exposure and those that are not, but also based on their mutational signatures, anatomic site, and epidemiology. The incidence of melanoma skin cancer has been increasing over the past decades with 132,000 cases occurring globally each year. Marine organisms have been shown to be an excellent source of natural compounds with possible bioactivities for human health applications. In this review, we report marine compounds from micro- and macro-organisms with activities in vitro and in vivo against melanoma, including the compound Marizomib, isolated from a marine bacterium, currently in phase III clinical trials for melanoma. When available, we also report active concentrations, cellular targets and mechanisms of action of the mentioned molecules. In addition, compounds used for UV protection and melanoma prevention from marine sources are discussed. This paper gives an overview of promising marine molecules which can be studied more deeply before clinical trials in the near future.

Multiple Myeloma: Possible Cure from the Sea.

Multiple myeloma (MM) is a blood cancer that occurs in the plasma cells (PCs), a type of white blood cell. Despite the progress of several current treatments that prolong the overall patient's survival, most MM cases are incurable. For this reason, many efforts have been undertaken by the scientific community in the search for new treatments. BLENREPTM and Aplidin® are two marine-derived drugs currently in use for MM. In addition, other natural products have been identified from marine organisms, tested for their possible anticancer properties, and are in preclinical or clinical trials for MM, including cytarabine, a compound in use for leukaemia treatment. Between the most successful marine compounds in fighting MM, there are molecules with specific targets, such as the elongation factor 1-alpha 2 and proteasome inhibitors, and compounds conjugated with antibodies that recognise specific cell types and direct the drug to the correct cell target. Active compounds belong to different chemical classes, from cyclic peptides to alkaloids, highlighting the importance of screening the plethora of compounds produced by marine organisms. In this review, we summarise the current state of art of MM therapies focusing on the marine natural product emerging roles.

Auto-regulation of Secretory Flux by Sensing and Responding to the Folded Cargo Protein Load in the Endoplasmic Reticulum.

Maintaining the optimal performance of cell processes and organelles is the task of auto-regulatory systems. Here we describe an auto-regulatory device that helps to maintain homeostasis of the endoplasmic reticulum (ER) by adjusting the secretory flux to the cargo load. The cargo-recruiting subunit of the coatomer protein II (COPII) coat, Sec24, doubles as a sensor of folded cargo and, upon cargo binding, acts as a guanine nucleotide exchange factor to activate the signaling protein Gα12 at the ER exit sites (ERESs). This step, in turn, activates a complex signaling network that activates and coordinates the ER export machinery and attenuates proteins synthesis, thus preventing large fluctuations of folded and potentially active cargo that could be harmful to the cell or the organism. We call this mechanism AREX (autoregulation of ER export) and expect that its identification will aid our understanding of human physiology and diseases that develop from secretory dysfunction.

Control systems of membrane transport at the interface between the endoplasmic reticulum and the Golgi.

A fundamental property of cellular processes is to maintain homeostasis despite varying internal and external conditions. Within the membrane transport apparatus, variations in membrane fluxes from the endoplasmic reticulum (ER) to the Golgi complex are balanced by opposite fluxes from the Golgi to the ER to maintain homeostasis between the two organelles. Here we describe a molecular device that balances transport fluxes by integrating transduction cascades with the transport machinery. Specifically, ER-to-Golgi transport activates the KDEL receptor at the Golgi, which triggers a cascade that involves Gs and adenylyl cyclase and phosphodiesterase isoforms and then PKA activation and results in the phosphorylation of transport machinery proteins. This induces retrograde traffic to the ER and balances transport fluxes between the ER and Golgi. Moreover, the KDEL receptor activates CREB1 and other transcription factors that upregulate transport-related genes. Thus, a Golgi-based control system maintains transport homeostasis through both signaling and transcriptional networks.

Golgi-dependent signaling: self-coordination of membrane trafficking.

Multiple studies have shown that endomembranes can act as signaling platforms for plasma-membrane-originated signaling. In particular, the Golgi complex operates as a relay station for signaling, which is initiated by classical ligand-receptor systems at the plasma membrane, acting as a positive or negative regulator of these plasma-membrane signals. Thus, the Golgi complex has emerged as a hub for intracellular signaling. Furthermore, recent evidence has indicated that the Golgi complex can also trigger its own signaling cascades, which involve some of the molecular players that are classically engaged in signal transduction at the plasma membrane. This aspect of the Golgi complex, namely, the ability to generate autonomous signaling, has been experimentally addressed only in the last few years. These studies have revealed that the transport vesicles that leave the ER for the Golgi complex also carry signal molecules that can then be sensed by a receptor in the Golgi complex to coordinate secretory organelles. The receptor involved in the sensing of incoming traffic at the Golgi complex has been shown to be the KDEL receptor (KDELR), a proposed new G-protein-coupled receptor. Upon binding to a KDEL-containing ligand (a chaperone), the KDELR can activate a signaling cascade that regulates anterograde intra-Golgi trafficking. However, this Golgi-based signaling response is only partially understood to date. Here we report on several approaches that are suitable for the study of traffic-initiated and KDELR-dependent signaling.

Noninvasive repetitive imaging of somatostatin receptor 2 gene transfer with positron emission tomography.

Noninvasive in vivo imaging of gene expression is desirable to monitor gene transfer in both animal models and humans. Reporter transgenes with low endogenous expression levels are instrumental to this end. The human somatostatin receptor 2 (hSSTR2) has low expression levels in a variety of tissues, including muscle and liver. We tested the possibility of noninvasively and quantitatively monitoring hSSTR2 transgene expression, following adeno-associated viral (AAV) vector-mediated gene delivery to murine muscle and liver by positron emission tomography (PET) using (68)gallium-DOTA-Tyr(3)-Thr(8)-octreotate ((68)Ga-DOTATATE) as a highly specific SSTR2 ligand. Repetitive PET imaging showed hSSTR2 signal up to 6 months, which corresponds to the last time point of the analysis, after gene delivery in both transduced tissues. The levels of tracer accumulation measured in muscle and liver after gene delivery were significantly higher than in control tissues and correlated with the doses of AAV vector administered. As repetitive, quantitative, noninvasive imaging of AAV-mediated SSTR2 gene transfer to muscle and liver is feasible and efficient using PET, we propose this system to monitor the expression of therapeutic genes coexpressed with SSTR2.

Long-term amelioration of feline Mucopolysaccharidosis VI after AAV-mediated liver gene transfer.

Mucopolysaccharidosis VI (MPS VI) is caused by deficient arylsulfatase B (ARSB) activity resulting in lysosomal storage of glycosaminoglycans (GAGs). MPS VI is characterized by dysostosis multiplex, organomegaly, corneal clouding, and heart valve thickening. Gene transfer to a factory organ like liver may provide a lifetime source of secreted ARSB. We show that intravascular administration of adeno-associated viral vectors (AAV) 2/8-TBG-felineARSB in MPS VI cats resulted in ARSB expression up to 1 year, the last time point of the study. In newborn cats, normal circulating ARSB activity was achieved following delivery of high vector doses (6 × 10(13) genome copies (gc)/kg) whereas delivery of AAV2/8 vector doses as low as 2 × 10(12) gc/kg resulted in higher than normal serum ARSB levels in juvenile MPS VI cats. In MPS VI cats showing high serum ARSB levels, independent of the age at treatment, we observed: (i) clearance of GAG storage, (ii) improvement of long bone length, (iii) reduction of heart valve thickness, and (iv) improvement in spontaneous mobility. Thus, AAV2/ 8-mediated liver gene transfer represents a promising therapeutic strategy for MPS VI patients.

Different serum enzyme levels are required to rescue the various systemic features of the mucopolysaccharidoses.

Mucopolysaccharidoses (MPSs) are lysosomal storage disorders characterized by progressive accumulation of glycosaminoglycans (GAGs) in various tissues. Enzyme replacement therapy (ERT) for several MPSs is available to date. However, the efficacy of ERT is limited, in particular in compartments such as bone, cartilage, the brain, and the eyes. We selected a rodent model of an MPS, with no central nervous system storage, to study the impact, on systemic features of the disease, of various stable levels of exogenous enzymes produced by adeno-associated viral vector (AAV)-mediated liver gene transfer. Low levels (6% of normal) of circulating enzyme were enough to reduce storage and inflammation in the visceral organs and to ameliorate skull abnormalities; intermediate levels (11% of normal) were required to reduce urinary GAG excretion; and high levels (>or=50% of normal) rescued abnormalities of the long bones and motor activity. These data will be instrumental to design appropriate clinical protocols based on either enzyme or gene replacement therapy for MPS and to predict their impact on the pathological features of MPS.