Lichen secondary metabolites in Flavocetraria cucullata exhibit anti-cancer effects on human cancer cells through the induction of apoptosis and suppression of tumorigenic potentials

PLoS One. 2014 Oct 31;9(10):e111575. doi: 10.1371/journal.pone.0111575. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Annexin A5 / metabolism
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Benzofurans / pharmacology
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology*
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • G1 Phase / drug effects
  • Humans
  • Lichens / chemistry*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Secondary Metabolism / drug effects*

Substances

  • Annexin A5
  • Antineoplastic Agents
  • Benzofurans
  • usnic acid
  • Proto-Oncogene Proteins c-akt

Grant support

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF-2013R1A1A2004677, NRF-2013R1A2A2A07067609) and by the Korea National Research Resource Center Program (NRF-2012M3A9B8021726). This study also received support from a research grant funded by the Sunchon Research Center for Natural Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.