Biological activities of sinularin: A literature-based review

Sinularin ((9E)-13-hydroxy-4,9,13-trimethyl-17-methylidene-5,15-dioxatricyclo[12.3.1.0(4,6)] octadec-9-en-16-one) is the soft coral-derived hopeful biologically active lead compound. In this review sinularin biological activities are summarized. For that, an up-to-date (from 1980 to Mar 2020) search was made in the PubMed, Science Direct, Web of Science, Scopus, The American Chemical Society, Clinicaltrials.gov, and Google Scholar databases. Data available suggest that sinularin has interesting anti-inflammatory, anticancer, anti-fouling and analgesic potential. The inducible nitric oxide synthase (iNOS), cyclooxigenase (COX)-2, tumor growth factor beta 1 (TGF-β1) are the most efficient enzymes for interacting with sinularin due to its anti-inflammatory activity, while phosphoinositol 3-kinase (PI3K), Akt and mechanistic target of rapamycin (mTOR) for its anticancer effect. In conclusion, sinularin seems to be a promissory lead compound in the treatment of inflammation, cancer and neurological disorders.


Introduction
The oceans are home to around 90% of the world's living biomass, therefore, the marine environment is an extraordinary and rich reservoir of bioactive natural products with multiple pharmacological potentialities (1). Sinularin is a natural compound isolated from marine soft corals (e.g., Sinularia triangular, S. querciformis, S. flexibilis), and increasing evidences have suggest that it possess some important biological effects, including anti-inflammatory and analgesic, anti-fouling and anticancer effects (2,3,8,9). Nonetheless, although it has been isolated and identified 30 years ago, scientific reports regarding its biological effects are not enough.
In this sense, the present review aims to sketch the current scenario on sinularin biological effects based on scientific reports from various databases.

Methods
An up-to-date (till Mar 2020) search was made in the PubMed/MedLine, Science Direct, Web of Science, clinicaltrials.gov, and Google Scholar databases, selecting as main keyword "sinularin", which was then paired with the following keywords "biological sources", "biological effects", "pharmacological activity", and "toxicology". Scientific reports were then target of a strict scrutiny and analyzed considering the following inclusion and exclusion criteria.

Inclusion criteria
1. Studies carried out in vitro, ex vivo, in vivo, in silico with or without using experimental animals, including humans and their derived tissue and cells; 2. Studies with sinularin and its derivatives or preparations; 3. Studies with or without proposing activity mechanisms; 4. Studies regard to any biological/pharmacological activity.

Exclusion criteria
1. Duplication of data and titles and/or abstracts (in the databases) or not meeting the inclusion criteria; and 2. Studies on crude coral extract having no information on sinularin presence/determination.
After application of the above-mentioned filters, a total of 13 scientific reports were found, and selected to be discussed here.

Biological effects of sinularin
Over the years, several biological activities have been proposed and increasingly confirmed to sinularin, namely with concerns to its anti-inflammatory, analgesic, anticancer, and anti-fouling effects (Table 1).
10, 50, 100 µg/mL in Bugula neritina and Balanus albicostatus Anti-fouling activity (EC 50 : >100 µg/mL)  TGF-β1 is more potent than certain types of interleukins (ILs) stimulus, such as IL-1β (20). Sinularin also exerts analgesic effects in rats and RAW 264.7 cells by downregulating TGF-β1 expression (2). Cancer constitutes a huge society burden in more and less economically developed countries worldwide (21). It has been reported that, the occurrence of cancer is increasing day-by-day (22). It is due to the population growth and aging, along with a raising prevalence of established risk factors (e.g., smoking, overweight, physical inactivity) and changing reproductive patterns associated with urbanization and economic development (23). Accumulated reports have demonstrated that natural products possess effective anti-cancer effects and may serve as alternative tools for cancer treatment (24). Approximately 50 years since the cytarabine (a marinederived anticancer drug) approval, 4 approved drugs and 18 agents were target of clinical trials, 6 of which are in late development. However, in the recent decade, the discovery and development of anti-cancer drugs from marine origin has gaining much attention (25). According to the scientific evidence, sinularin was found to act against a number of cancer cell lines through distinct pathways, thus suggesting its promising and multiedged sword-like anti-cancer effects. The possible anticancer pathways of sinularin in cultured cancer cells are briefly pictured in Figure 1.

Conclusion
Taken together, data related to sinularin bioactive effects markedly point out its prominent anti-inflammatory, anticancer, anti-fouling and analgesic potentialities. Its anti-inflammatory effects are due to iNOS, COX enzymes (especially COX-2) and TGF-β1 inhibition, while the anti-cancer activity have been proposed to be promoted through interaction with PI3K, Akt and mTOR-dependent pathways. Of note, sinularin may be one of the hopeful marine-derived therapeutic tools in the treatment of inflammation, cancer and neurological ver, sinularin (7.5, 15, 30, 60 µM) also caused oxidative DNA damage and cell cycle arrest at G2/M phase and resulted in apoptotic cell death through PARP, caspases-3, -8, and -9-dependent pathways in breast cancer (SKBR3 and MDA-MB-231) cell lines (9). Sinularin (5-80 µM) was also able to activate caspase-3/-9, release mitochondrial proteins, up-regulate pro-apoptotic Bcl-2 family proteins and inhibit anti-apoptotic Bcl-2 family proteins (10). In this study, it was also found to downregulate PI3K/Akt/mTOR signaling pathway, while upregulate MAPKs and p38 signaling pathways in human renal (786-O and ACHN) cancer cells.

Discussion
Inflammation is part of the complex biological response of body tissues to harmful stimuli, including pathogens (e.g., bacteria, virus), damaged cells, or even irritants. It is a protective response governed by immune cells, blood vessels, and molecular mediators. Generally, this process eliminates the initial cause of cell injury, clear out necrotic cells and damaged tissues from the original insult and other inflammatory processes, and initiate tissue repair (14). However, it is evident that human beings' aging is characterized by a chronic, low-grade inflammation, better to be termed as "inflammaging", a highly pronounced risk factor for both morbidity and mortality in the elderly population due to inflammatory pathogenesis (15).
Nitric oxide synthases (NOS) are a family of isoforms responsible for the synthesis of the potent dilator nitric oxide (NO). Generally, iNOS expression occurs in inflammatory conditions, and produces large amounts of NO, which is one of the leading causes of cardiovascular diseases, such as atherosclerosis (16). On the other hand, COX-2 is a key enzyme in fatty acid metabolism, that is upregulated during both inflammation and cancer. It is induced by pro-inflammatory cytokines at the site of inflammation and enhances the synthesis of prostaglandins, stimulates cancer cell proliferation, promotes angiogenesis, inhibits apoptosis, and increases the metastatic potential. Therefore, COX-2 inhibitors are target of intense research interest toward potential clinical applications (17).
LPS acts as the prototypical endotoxin because it binds the CD14/TLR4/MD2 receptor complex in many cell types, such as monocytes, dendritic cells, macrophages and B cells, promoting the secretion of many inflammatory mediators, among them pro-inflammatory cytokines and NO (18). In a study, sinularin has shown to be able to inhibit the upregulated pro-inflammatory proteins, including iNOS and COX-2 in LPS-stimulated murine macrophage cells (12).
The interplay between nerve growth factor (NGF) and pain perception or other nervous system-related functions may directly influence growth factors and cytokines, such as tumor necrosis factor (TNF)-α and TGF-β1 in many cells, including human, murine, and bovine chondrocytes (19,20). This induction of NGF by diseases. Further studies are necessary to assess other sinularin-related pharmacological and toxicological effects in animal models.