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Friday, February 17, 2017

What are the therapeutic properties of the natural product cynaropicrin from artichoke?

Abstract (as presented by the authors of the scientific work):

"The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway). These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV."

Covered topics (the letter size corresponds to the frequency of mentioning in the text):

Discussion and conclusions (as presented by the authors of the scientific work):

"Cynaropicrin has multi-medicinal potential therapeutics evidenced not just by the ample scientific literature describing it, but also by the plenty number of patent applications (http://www.thegoodscentscompany.com/data/rw1701261.html, accessed 28-2-2016). The most outstanding activity recently discovered for cynaropicrin is the activity against HCV where it presents a very attractive pan-genotypic anti-HCV natural product. It showed potent and broad spectrum potential against the major genotypes of HCV by inhibiting viral cell entry.

The discovery of novel anti-HCV entry inhibitors such as cynaropicrin could help to develop preventive therapies/measures against hepatitis C where immunization against HCV is at present unavailable due to the highly mutable nature of the virus. Important applications of entry inhibitors include the prevention of recurrence in the new liver in HCV-patients after liver transplantation. In patients with HCV-related end-stage liver diseases undergoing liver transplantation, re-infection of the graft is universal and characterized by accelerated progression of liver diseases. Entry inhibitors may be effective especially in these patients undergoing violent re-infection of HCV into hepatocytes (Nakajima et al., 2013).

From the histo-pharmacology of cynaropicrin action, it seems that most of its pharmacological effects are convergent to support the anti-HCV activity, as follows:

(1) Cynaropicrin was found to suppress hyperlipidaemia as mentioned above (Shimoda et al., 2003). The lipids are important factors for the life-cycle of HCV where the virus replication and assembly is dependent on host cell lipid metabolism. HCV attaches itself to lipids and very-low-density lipoproteins after its release from the infected cells. It will then circulate in the blood in the form of triglyceride-rich particles (Burlone and Budkowska, 2009). It was also demonstrated that HCV-core protein (C), and the non-structural proteins NS2 and NS5A of HCV induce lipid accumulation in the liver cells resulting in steatosis, fatty liver and potential progression of liver disease and associated with hepatic inflammation and fibrosis. Therefore, it is important to lower increased cholesterol and triglycerides concentrations in HCV-infected patients (Kim et al., 2009).

(2) Cynaropicrin is a potent antioxidant (Takei et al., 2015; Yamada et al., 2015) and hence it can play a supportive role for liver in different hepatic diseases. Oxidative stress plays an important role in the pathogenesis of chronic hepatitis C. Oxidative stress occurs early during HCV infection and increases with disease progression and severity and hence the infected patient with HCV is usually being advised to take antioxidants such as vitamins C, D, and E, which are the most investigated as antioxidant therapy in chronic liver diseases (Milliman et al., 2000).

(3) Cynaropicrin is a potent inhibitor of TNF-α action which is a major mediator of the inflammatory process in HCV patients. Serum levels of TNF-α have been correlated with elevated alanine aminotransferase (ALT) and increased severity of fibrosis in HCV patients. Patients receiving interferon showed decreased TNF-α concentration (Milliman et al., 2000). It is also suggested that the activation of the NF-κB and AKT pathways are involved in increased HCV replication (Brenndörfer et al., 2009).

(4) Since cancer is the result of a deregulation of multiple signaling pathways and cynaropicrin elicit multi-targeted activities, this natural product could hold a great potential for treating human tumors. Cynaropicrin having significant antitumor activity and it may be served as potential cancer chemopreventive lead drug for prevention or treatment of human cancers (Kang et al., 2007). Human infection with HCV is currently recognized as the leading cause of the severe complications such as HCC which demands liver transplantation (Ishida et al., 2014) since HCC is the major histological subtype of primary liver cancer (Hu et al., 2013). A total of ~27% of individuals that develop liver cirrhosis and HCC worldwide arise in HCV-infected people (Ishida et al., 2014). It appears to be the major causative factor responsible for the recent doubling of HCC which was estimated to result in ~10,000 deaths in the United States only in the year 2011 (Gonzalez et al., 2009; Ibrahim et al., 2013). Cynaropicrin has anti-inflammatory, anti-tumor, TNF-α inhibitory, and antioxidant activities and hence it can also prevent the progression of HCC. Indeed, most natural agents do not induce a high level of toxicity and target multiple signaling pathways involved in cell growth, invasion, apoptosis, angiogenesis and metastasis (Pulito et al., 2015).

Cynaropicrin as a potential therapeutic compound is having many other advantages:

(1) The cynaropicrin is one of the main active constituents of artichoke; the therapeutic effects of the latter have been observed in several clinical trials (Giacosa et al., 2015) and it has recently attracted attention because of its well-proven safety at concentrations currently employed in alcoholic beverages (Cravotto et al., 2005). Another clinical study recommended artichoke extract for treating hyperlipoproteinemia and, thus, prevention of atherosclerosis and coronary heart disease and showed that there were no drug-related adverse events indicating an excellent tolerability of artichoke extract (Englisch et al., 2000). Artichoke is a fundamental component of Mediterranean diet and is available globally in all markets (Pulito et al., 2015). (2) The compound is water-soluble and hence therapeutic injections can be formulated which will decrease the amount of dosage form and shorten the duration of therapy and thus reducing putative side effects.

(3) The compound has a simple structure and hence it can be synthesized and marketed with affordable prices.

The final conclusion is that cynaropicrin is a very effective and promising natural product for hepatitis C virus infection and a prospective new drug lead, since it has a direct action on HCV by cell entry inhibition and cell-cell coinfection inhibition and also it may exert inhibitory effects on HCV replication via suppression of one or more signaling pathways related to ROS, Akt, NF-κB, and STAT3. Further in-depth studies including clinical trials are needed to fully evaluate its value for HCV treatment. Thus, cynaropicrin represents a natural product with an excellent therapeutic potential that can be considered as one illustrative example in line with the re-emerging notion that medicinal plants are expected to be a continues magnificent source of molecules with therapeutic potential (Atanasov et al., 2015)."

The referenced scientific work at PubMed:

Elsebai MF, Mocan A, Atanasov AG. Cynaropicrin: A Comprehensive Research
Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent. Front
Pharmacol. 2016 Dec 8;7:472. doi: 10.3389/fphar.2016.00472. Review. PubMed PMID: 
28008316; PubMed Central PMCID: PMC5143615.

Full-text access:


Prof. Atanas G. Atanasov (Dr. habil., PhD)

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