Potassium usnate, a water-soluble usnic acid salt, shows enhanced bioavailability and inhibits invasion and metastasis in colorectal cancer

Abstract

Usnic acid (UA), a lichen secondary substance, has considerable anticancer activity in vitro, whereas its effect in vivo is limited. Here, potassium usnate (KU) was prepared by the salinization of UA to enhance its water solubility. KU showed increased bioavailability compared with UA in the tumor, liver, and plasma of a CT26 syngeneic mouse tumor xenograft model after oral administration, as determined by LC-MS/MS analysis. KU exhibited potent anticancer effects on colorectal cancer cells and inhibited liver metastasis in an orthotopic murine colorectal cancer model. KU treatment downregulated the epithelial-mesenchymal markers Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in cells and tumor tissues. The present results suggest the potential application of the water-soluble form of UA, KU, in anticancer therapy.

Anticancer Potential of Lichens’ Secondary Metabolites

“…Potassium usnate inhibited the growth of colorectal cancer cells and inhibited liver metastasis probably through the reduction of EMT markers such Twist, Snail, and Slug and the metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in this model. In addition, PU did not have any hepatotoxic effect in the mouse liver metastasis model [34]. Interestingly, ethyl acetate extract of Usnea longissima prevented esophagogastric adenocarcinoma induced by oral administration of N-methyl-N-nitro-N-nitrosoguanidin in Albino Wistar male rats.…”

“…Interestingly, anticancer potential of lichens can also be maintained by modulation of pathways associated with the cancer invasiveness such as c-Met, which acts as mesenchymal epithelial transition factor regulating PI3K/Akt/mTOR, Paxillin/Rac-1, and STATs signaling cascades [33]. Despite regulation of STAT3 activity, [20,34] lichens target β-catenin or its downstream effectors that consequently lead to the modulation of Wnt/β-catenin target genes including the cell cycle regulating genes (c-myc, cyclin D1) as well as genes associated with cell migration (MMP7), apoptosis (BIRC5) or other regulators such as Axin2 [20,26]. Additionally, regulation of c-Jun and c-fos, members of the AP-1 family of critical regulators of gene expression and reduction of KITENIN-mediated AP-1 activity are also associated with anticancer mechanisms of lichens [20].…”

“…Potasium usnate showed stronger inhibitory effects on the invasion of Caco2 and HCT116 cells compared to UA. Importantly, PU downregulated the epithelial-mesenchymal markers (EMT) including Twist, Snail, and Snug and decreased the expression of metastasis-related genes CAPN1, CDC42, CFL1, IGF1, WASF1, and WASL in Caco2 cells [34]. An anticancer efficacy of UA was evaluated together with diffractaic acid (DA) and lobaric acid (LA) in human glioblastoma multiforme (U87MG-GBM) and rat cerebral cortex cells (PRCC).…”

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

“…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. Moreover, the enamine derivative of UA (11) also selectively inhibited the activity of PARP1 (17% residual activity, 7-fold in comparison with D N A p o l y m e r a s e β ) .…”

A facile in vivo procedure to analyze metabolic pathways in intact lichens

“…This compound was proposed to serve as a food supplement for weight loss, although hepatotoxic effects also were reported (Hsu et al ., ; Sonko et al ., ; Yellapu et al ., ). Nevertheless, usnic acid was shown to exhibit many other beneficial properties, such as being antiviral against hepatitis C and influenza viruses (Shtro et al ., , ; Wei et al ., ), antibacterial against Mycobacterium tuberculosis (Ramos & Almeida da Silva, ; Cirillo et al ., ) and Gram‐positive bacteria including Staphylococcus aureus (Francolini et al ., ; Paudel et al ., ; Pompilio et al ., ; Tozatti et al ., ), anti‐protozoal (Sussmann et al ., ), anti‐helmintic (Araújo et al ., ), anti‐mitotic (al‐Bekairi et al ., ; Cardarelli et al ., ), anti‐inflammatory (Vijayakumar et al ., ), analgesic (Okuyama et al ., ), anti‐cancer (Yang et al ., ) and herbicidal (Romagni et al ., ). Moreover, the compound absorbs UV light making it a potential ingredient in sunscreen products (Legouin et al ., ).…”