Lichen Secondary Metabolites in Flavocetraria cucullata Exhibit Anti-Cancer Effects on Human Cancer Cells through the Induction of Apoptosis and Suppression of Tumorigenic Potentials

Abstract

Lichens are symbiotic organisms which produce distinct secondary metabolic products. In the present study, we tested the cytotoxic activity of 17 lichen species against several human cancer cells and further investigated the molecular mechanisms underlying their anti-cancer activity. We found that among 17 lichens species, F. cucullata exhibited the most potent cytotoxicity in several human cancer cells. High performance liquid chromatography analysis revealed that the acetone extract of F. cucullata contains usnic acid, salazinic acid, Squamatic acid, Baeomycesic acid, d-protolichesterinic acid, and lichesterinic acid as subcomponents. MTT assay showed that cancer cell lines were more vulnerable to the cytotoxic effects of the extract than non-cancer cell lines. Furthermore, among the identified subcomponents, usnic acid treatment had a similar cytotoxic effect on cancer cell lines but with lower potency than the extract. At a lethal dose, treatment with the extract or with usnic acid greatly increased the apoptotic cell population and specifically activated the apoptotic signaling pathway; however, using sub-lethal doses, extract and usnic acid treatment decreased cancer cell motility and inhibited in vitro and in vivo tumorigenic potentials. In these cells, we observed significantly reduced levels of epithelial-mesenchymal transition (EMT) markers and phosphor-Akt, while phosphor-c-Jun and phosphor-ERK1/2 levels were only marginally affected. Overall, the anti-cancer activity of the extract is more potent than that of usnic acid alone. Taken together, F. cucullata and its subcomponent, usnic acid together with additional component, exert anti-cancer effects on human cancer cells through the induction of apoptosis and the inhibition of EMT.

Anticancer Potential of Lichens’ Secondary Metabolites

“…Sub-lethal concentrations of this extract and UA inhibited tumorigenesis and motility of cancer cells, suppressed epithelial-mesenchymal transition (EMT) and inhibited Akt phosphorylation. Interestingly, the anticancer activity of the extract was more potent than that of UA [87].…”

Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

“…Inhibition of enzymes engaged in the DNA repair can be an efficient way to potentiate anticancer therapies which target DNA integrity. The pyrazole derivatives of UA (18)(19)(20)(21)(22)(23)(24)(25), especially compound 24 (Fig. 1, compound J), and their hydrazones (26)(27)(28)(29)(30) were found to be more selective inhibitors of PARP1, as the residual activity of polymerase β exceeded that of PARP1 by 2-5-fold, with the exception of compound 31 exhibiting the same effect on both enzymes.…”

“…Mitochondrial impairment, such as a drop in mitochondrial membrane potential, oxidative phosphorylation inhibition, ROS production, swelling, drop in ATP level and adaptive overexpression of genes associated with the electron transport chain, the Krebs cycle and lipid metabolism, have been shown to occur in the in vivo and/or in vitro models (cultured hepatocytes or cancer cells), as well as in isolated mitochondria [6,7,11,[13][14][15][16][17]. Such events lead to mitochondrial pathway of apoptosis [18][19][20][21][22], necrosis [15] and autophagy [14, 18, 23••]. Moreover, it has been shown that proton shuttling properties of UA also affect lysosomes in the breast cancer cells (T47D, MCF-7 cell lines), but not in the normal skin fibroblasts.…”

The Anticancer Activity of Cetraria Islandica (L.) Ach in Breast Cancer Cells Through Crosstalk of Ampk-α1 and Erk1/2 Signalling

“…It has suggested that lichens and their secondary metabolites can be used as an alternative method for the treatment of cancers (Kosanic et al, 2013(Kosanic et al, , 2014 due to its immune stimulation effect (Colak, et al, 2013). Recently, studies intended to show the effects of lichen extracts on various types of cancer are increasing (Coskun et al, 2015;Çelikler Kasımoğulları et al, 2014;He et al, 2010;Yang et al, 2014). One of the most studied lichen species is Cetraria islandica (Bessadottir et al, 2015) also known as Iceland Moss (Xu et al, 2016).…”