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Cells were treated with different concentrations (2.5\u2013100\u2009\u03bcM) of these compounds for 48\u2009h. In this comparative study, our lichen metabolites showed various cytotoxic effects in a concentration\u2010dependent 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\u2010diphenyl\u20102\u2010picrylhydrazyl (DPPH) assay. The lichen metabolites did not significantly increase the intracellular ROS level and did not prevent oxidative injury induced by <jats:italic>t<\/jats:italic>\u2010butylhydroperoxide 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\u20103, 8 and 9. Our results revealed that the antiproliferative activity of 40\u2009\u03bcM protolichesterinic acid in HeLa cells is related to its ability to induce programmed cell death involving caspase\u20103, 8 and 9 activation. 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