Download PDF
CC BY-NC-ND 4.0 · Planta Med 2022; 88(11): 891-898
DOI: 10.1055/a-1579-6454
Biological and Pharmacological Activity
Original Papers

The Anti-Proliferative Lichen-Compound Protolichesterinic Acid Inhibits Oxidative Phosphorylation and Is Processed via the Mercapturic Pathway in Cancer Cells

Freyr Jóhannsson
1   Faculty of Medicine, University of Iceland, Reykjavik, Iceland
,
Paulina Cherek
1   Faculty of Medicine, University of Iceland, Reykjavik, Iceland
,
Maonian Xu
2   Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavik, Iceland
,
Óttar Rolfsson
1   Faculty of Medicine, University of Iceland, Reykjavik, Iceland
,
Helga M. Ögmundsdóttir
1   Faculty of Medicine, University of Iceland, Reykjavik, Iceland
› Author AffiliationsSupported by: University of Iceland Research Fund
› Further Information
   Permissions and Reprints

Abstract

The lichen compound protolichesterinic acid (PA) has an anti-proliferative effect against several cancer cell lines of different origin. This effect cannot be explained by the known inhibitory activity of PA against 5- and 12-lipoxygenases. The aim was therefore to search for mechanisms for the anti-proliferative activity of PA. Two cancer cell lines of different origin, both sensitive to anti-proliferative effects of PA, were selected for this study, T-47D from breast cancer and AsPC-1 from pancreatic cancer. Morphological changes were assessed by transmission electron microscopy, HPLC coupled with TOF spectrometry was used for metabolomics, mitochondrial function was measured using the Agilent Seahorse XFp Real-time ATP assay and glucose/lactate levels by radiometry. Levels of glutathione, NADP/NADPH and reactive oxygen species [ROS] were measured by luminescence. Following exposure to PA both cell lines showed structural changes in mitochondria that were in line with a measured reduction in oxidative phosphorylation and increased glycolysis. These changes were more marked in T-47D, which had poorer mitochondrial function at baseline. PA was processed and expelled from the cells via the mercapturic pathway, which consumes glutathione. Nevertheless, glutathione levels were increased after 24 hours of exposure to PA, implying enhanced synthesis. Redox balance was not much affected and ROS levels were not increased. We conclude that PA is metabolically processed and expelled from cells, leading indirectly to increased glutathione levels with minimal effects on redox balance. The most marked effect was on mitochondrial structure and metabolic function implying that effects of PA may depend on mitochondrial fitness.

Key words

Protolichesterinic acid - mitochondria - cancer - metabolism - Cetraria islandica - Parmeliaceae

Supporting Information

    Supplementary Figure 1: Glucose uptake and lactate secretion. Supplementary Figure 2: Mass spectra and molecular structure of protolichesterinic acid (PA) and PA conjugates measured with qTOF tandem mass spectrometry. Supplementary Figure 3: Changes to derivatives of lysophosphatidyl choline and carnitine. Supplementary Figure 4: Trends towards lowered ROS following PA treatment.

  • Supporting Information


Publication History

Received: 04 March 2021

Accepted after revision: 03 August 2021

Article published online:
14 September 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Xu M, Heidmarsson S, Thorsteinsdottir M, Kreuzer M, Hawkins J, Omarsdottir S, Olafsdottir ES. Authentification of Iceland Moss [Cetraria islandica] by UPLC-QToF-MS chemical profiling and DNA barcoding. Food Chem 2018; 245: 989-996
    CrossrefPubMedGoogle Scholar
  • 2 Xu M, Heidmarsson S, Olafsdottir ES, Buonfiglio R, Kogej T, Omarsdottir S. Secondary metabolites from cetrarioid lichens: Chemotaxonomy, biological activities and pharmaceutical potential. Phytomedicine 2016; 23: 441-459
    CrossrefPubMedGoogle Scholar
  • 3 Ogmundsdóttir HM, Zoëga GM, Gissurarson SR, Ingólfsdóttir K. Anti-proliferative effects of lichen-derived inhibitors of 5-lipoxygenase on malignant cell-lines and mitogen-stimulated lymphocytes. J Pharm Pharmacol 1998; 50: 107-115
    CrossrefPubMedGoogle Scholar
  • 4 Haraldsdóttir S, Gudlaugsdóttir E, Ingólfsdóttir K, Ogmundsdóttir HM. Anti-proliferative effects of lichen-derived lipoxygenase inhibitors on twelve human cancer cell lines of different tissue origin in vitro . Planta Med 2004; 70: 1098-1100
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Brisdelli F, Perilli M, Sellitri D, Piovano M, Garbarino JA, Nicoletti M, Bozzi A, Amicosante G, Celenza G. Cytotoxic activity and antioxidant capacity of purified lichen metabolites: an in vitro study. Phytother Res 2013; 27: 431-437
    CrossrefPubMedGoogle Scholar
  • 6 Ingolfsdottir K, Breu W, Huneck S, Gudjonsdottir GA, Müller-Jakic B, Wagner H. In vitro inhibition of 5-lipoxygenase by protolichesterinic acid from Cetraria islandica. Int Immunopharmacol l 1994; 1: 187-191
    PubMedGoogle Scholar
  • 7 Bucar F, Schneider I, Ogmundsdóttir H, Ingólfsdóttir K. Anti-proliferative lichen compounds with inhibitory activity on 12[S]-HETE production in human platelets. Int Immunopharmacol 2004; 11: 602-606
    PubMedGoogle Scholar
  • 8 Pidgeon GP, Lysaght J, Krishnamoorthy S, Reynolds JV, OʼByrne K, Nie D, Honn KV. Lipoxygenase metabolism: roles in tumor progression and survival. Cancer Metastasis Rev 2007; 26: 503-524
    CrossrefPubMedGoogle Scholar
  • 9 Bessadóttir M, Eiríksson FF, Becker S, Ögmundsdóttir MH, Ómarsdóttir S, Thorsteinsdóttir M, Ögmundsdóttir HM. Anti-proliferative and pro-apoptotic effects of lichen-derived compound protolichesterinic acid are not mediated by its lipoxygenase-inhibitory activity. Prostaglandins Leukot Essent Fatty Acids 2015; 98: 39-47
    CrossrefPubMedGoogle Scholar
  • 10 Bessadóttir M, Skúladóttir E, Gowan S, Eccles S, Ögmundsdóttir S, Ogmundsdóttir HM. Effects of anti-proliferative lichen metabolite, protolichesterinic acid on fatty acid synthase, cell signalling and drug response in breast cancer cells. Phytomedicine 2014; 21: 1717-1724
    CrossrefPubMedGoogle Scholar
  • 11 Pengsuparp T, Cai L, Constant H, Fong HH, Lin LZ, Kinghorn AD, Pezzuto JM, Cordell GA, Ingolfsdóttir K, Wagner H. Mechanistic evaluation of new plant-derived compounds that inhibit HIV-1 reverse transcriptase. J Nat Prod 1995; 58: 1024-1031
    CrossrefPubMedGoogle Scholar
  • 12 Brinkman K, Kakuda TN. Mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors: a looming obstacle for long-term antiretroviral therapy?. Curr Opin Infect Dis 2000; 13: 5-11
    CrossrefPubMedGoogle Scholar
  • 13 Smith CA, Want EJ, OʼMaille G, Abagyan R, Siuzdak G. XCMS: processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification. Anal Chem 2006; 78: 779-787
    CrossrefPubMedGoogle Scholar
  • 14 Elia I, Broekaert D, Christen S, Boon R, Radaelli E, Orth MF, Verfaillie C, Grünewald TGP, Fendt SM. Proline metabolism supports metastasis formation and could be inhibited to selectively target metastasizing cancer cells. Nat Commun 2017; 8: 15267
    CrossrefPubMedGoogle Scholar
  • 15 Gunawardena G. Michael Addition. Accessed February 1, 2021 at: https://chem.libretexts.org/Ancillary_Materials/Reference/Organic_Chemistry_Glossary/Michael_Addition
    PubMedGoogle Scholar
  • 16 Punganuru SR, Madala HR, Arutla V, Srivenugopal KS. Selective killing of human breast cancer cells by the styryl lactone [R]-goniothalamin is mediated by glutathione conjugation, induction of oxidative stress and marked reactivation of the R175H mutant p;53 protein. Carcinogenesis 2018; 39: 1399-1410
    PubMedGoogle Scholar
  • 17 Lu SC. Glutathione synthesis. Biochim Biophys Acta 2013; 1830: 3143-3153
    CrossrefPubMedGoogle Scholar
  • 18 Le Lamer AC, Authier H, Rouaud I, Coste A, Boustie J, Pipy B. et al. Protolichesterinic acid derivatives: α-methylene-γ-lactones as potent dual activators of PPARγ and Nrf2 transcriptional factors. Bioorg Med Chem Lett 2014; 24: 3819-3822
    CrossrefPubMedGoogle Scholar
  • 19 Bensinger SJ, Christofk HR. New aspects of the Warburg effect in cancer cell biology. Semin Cell Dev Biol 2012; 23: 352-361
    CrossrefPubMedGoogle Scholar
  • 20 Grasso D, Zampieri LX, Capelôa T, Van de Velde JA, Sonveaux P. Mitochondria in cancer. Cell Stress 2020; 4: 114-146
    CrossrefPubMedGoogle Scholar
  • 21 Lee ST, Lawrentschuk N, Scott AM. PET in prostate and bladder tumors. Semin Nucl Med 2012; 42: 231-246
    CrossrefPubMedGoogle Scholar
  • 22 Picard M, Shirihai OS, Gentil BJ, Burelle Y. Mitochondrial morphology transitions and functions: implications for retrograde signaling?. Am J Physiol Regul Integr Comp Physiol 2013; 304: R393-R406
    CrossrefPubMedGoogle Scholar
  • 23 Jóhannsson F, Árnason N, Landrö R, Guðmundsson S, Sigurjonsson ÓE, Rolfsson Ó. Metabolomics study of platelet concentrates photochemically treated with amotosalen and UVA light for pathogen inactivation. Transfusion 2020; 60: 367-377
    CrossrefPubMedGoogle Scholar