The purpose of this study was to investigate the effects of six lichen metabolites (diffractaic acid, lobaric acid, usnic acid, vicanicin, variolaric acid, protolichesterinic acid) on proliferation, viability and reactive oxygen species (ROS) level towards three human cancer cell lines, MCF-7 (breast adenocarcinoma), HeLa (cervix adenocarcinoma) and HCT-116 (colon carcinoma). Cells were treated with different concentrations (2.5-100 μM) of these compounds for 48 h. In this comparative study, our lichen metabolites showed various cytotoxic effects in a concentration-dependent manner, and usnic acid was the most potent cytotoxic agent, while variolaric acid did not inhibit the proliferation of any of the three cell lines used. All tested lichen compounds did not exhibit free radical scavenging activity using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. The lichen metabolites did not significantly increase the intracellular ROS level and did not prevent oxidative injury induced by t-butylhydroperoxide in HeLa cells. To better clarify the mechanism(s) of cytotoxic effect induced by protolichesterinic acid in HeLa cells, we investigated apoptotic markers such as condensation and fragmentation of nuclear chromatin and activation of caspase-3, 8 and 9. Our results revealed that the antiproliferative activity of 40 μM protolichesterinic acid in HeLa cells is related to its ability to induce programmed cell death involving caspase-3, 8 and 9 activation.

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In the course of our continuing search for new natural anticancer compounds for treatment and/or prevention of prostate cancer, our laboratory has focused its search on poorly investigated lichen metabolites, sphaerophorin, pannarin and epiphorellic acid-1. To this end, we treated DU-145, a cell line resembling the last stage of prostate carcinoma, with different concentrations (6-50 micromol/l) of these compounds for 72 h. Our data clearly evidenced that these lichen metabolites inhibit the growth of human prostate carcinoma DU-145 cells, but pannarin exhibits a higher effect. Our data show an induction of apoptotic death of advanced prostate cancer cells by sphaerophorin, pannarin and epiphorellic acid-1. In fact, a significant (P<0.001) increase in caspase-3 enzyme activity occurred in DU-145 cells treated with all lichen compounds at 12 and 25 micromol/l concentrations, correlated to a high DNA fragmentation, but without the disruption of the plasma membrane, as evaluated by the percentage of lactic dehydrogenase release. Alternatively, we found a low, but significant (P<0.01) lactic dehydrogenase release at higher concentrations (50 micromol/l), suggesting that in these experimental conditions sphaerophorin, pannarin and epiphorellic acid-1 induce necrosis in DU-145 cells, through the increase in reactive oxygen species generation. The experimental evidence is further confirmed by caspase-3 activity results, evidencing a reduction in the activity of this protease at a higher concentration, 50 micromol/l.

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Secondary metabolites of lichens may be considered to be 'lead compounds' for the development of novel molecules for the treatment of S. aureus infections in cystic fibrosis patients.