Biological Effects of Gyrophoric Acid and Other Lichen Derived Metabolites, on Cell Proliferation, Apoptosis and Cell Signaling pathways

Abstract

Secondary metabolites from fungi, algae and lichens have remarkable biological activities as antibiotics, fungicides, antiviral drugs, and cancer therapeutics. This review focuses on the lichen-derived metabolite gyrophoric acid and other select secondary metabolites (e.g., usnic acid, salazinic acid, physodic acid, vulpinic acid ceratinalone, flavicansone, ramalin, physciosporin, tumidulin, atranorin, parmosidone) that modulate a number of cellular pathways relevant to several biomedical diseases and disorders, including cancer, diabetes and cardiovascular disease. We discuss the chemical structure and biochemical activities of gyrophoric acid and other compounds relative to the molecular mechanisms and cellular processes that these metabolites target in a distinct human and rodent cell types. The therapeutic promise of gyrophoric acid and similar lichen derived metabolites is associated with the chemical versatility of these compounds as polyaromatic depsides with functional carboxyl and hydroxyl side-groups that may permit selective interactions with distinct enzymatic active sites. Gyrophoric acid has been examined in a series of studies as an effective anticancer drug because it impinges on topoisomerase 1 activity, as well as causes cell cycle arrest, comprises cell survival, and promotes apoptosis. Because gyrophoric acid has cytostatic properties, its biological roles and possible medicinal utility may extend beyond effects on cancer cells and be relevant to any process that is controlled by cell growth and differentiation.

Keywords: Anticancer; Apoptosis; Cancer cytostatic; Cardiovascular diseases; Cytotoxic; Depside; Diabetes; Gyrophoric acid; Lichens; Mechanism of action; Proliferation; Secondary metabolite; Topoisomerase.

Figure 1:. Overview of biochemical activities of gyrophoric acid.

(A) Image of Umbilicaria muhlenbergii, a lichen species that is typically used for the extraction and isolation of secondary metabolites. These metabolites are chemically characterized by ultraviolet (UV), Fourier-transform infrared (FTIR), mass spectroscopy (MS), and nuclear magnetic resonance (NMR) spectroscopy. One of these secondary metabolites is gyrophoric acid, which is a polyaromatic compound with carboxyl and hydroxyl side chains that inhibits DNA topoisomerase and protein tyrosine phosphatase activities, while promoting DNA fragmentation, activation of the cell protective p53/p21 pathway and the proteolytic caspase cascade. (B) Tabular summary of studies that have examined the biochemical effects of gyrophoric acid on different types of enzymes (column 1), gene symbols of enzymes insofar appropriate (column 2), species or sources of the protein (column 3), the half-maximum inhibitory concentration (IC50) (column 4) and relevant references (column 5).

Figure 2:. Overview of cellular activities of gyrophoric acid.

The image shows a tabular summary of tumor cell lines and normal primary cell types (column 1), the biological origin (column 2) and species of the cells (column 3), the range of gyrophoric acid concentrations that were tested (column 4), cellular processes affected by gyrophoric acid (column 5) and relevant references (column 6).

Figure 3:

Diagram of apoptotic pathways activated by gyrophoric acid. The protein network shows anti-apoptotic and pro-apoptotic proteins known to be involved in induction of apoptosis, including proteins that respond to intracellular DNA damage and repair or extracellular apoptotic signals such as death domain receptors. The protein network was generated using proteins known to be involved in apoptosis based on gene ontology terms. String v11.0 was used to render a protein network using the highest stringency settings with removal of unconnected proteins.