Annonacin promotes selective cancer cell death via NKA-dependent and SERCA dependent pathways

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  • Andreas Yiallouris, School of Medicine, European University Cyprus, Nicosia, Cyprus
  • Ioannis Patrikios, School of Medicine, European University Cyprus, Nicosia, Cyprus
  • Elizabeth O. Johnson, School of Medicine, European University Cyprus, Nicosia, Cyprus
  • Evangelia Sereti, Department of Pharmacology, School of Health Sciences, University of Thessaly, Volos, Greece
  • Konstantinos Dimas, Department of Pharmacology, School of Health Sciences, University of Thessaly, Volos, Greece
  • Cristian De Ford, Department of Pharmaceutical Biology and Biotechnology, Spemann Graduate School of Biology and Medicine (SGBM), Albert Ludwigs University Freiburg, Freiburg, Germany
  • Natalya Fedosova
  • Wolfgang F. Graier, Gottfried Schatz Research Center, Molecular Biology & Biochemistry, Medical University of Graz, Graz, Austria
  • Kleitos Sokratous, Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus., Cyprus
  • Kyriakos Kyriakou, Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus., Cyprus
  • Anastasis Stephanou, School of Medicine, European University Cyprus, Nicosia, Cyprus

In the healthcare sector, phytocompounds are known to be beneficial by contributing or alleviating a variety of diseases. Studies have demonstrated the progressive effects of phytocompounds on immune-related diseases and to exhibit anticancer effects. Graviola tree is an evergreen tree with its extracts (leafs and seeds) been reported having anticancer properties, but the precise target of action is not clear. Using an in silico approach, we predicted that annonacin, an Acetogenin, the active agent found in Graviola leaf extract (GLE) to potentially act as a novel inhibitor of both sodium/potassium (NKA) and sarcoplasmic reticulum (SERCA) ATPase pumps. We were able to validate and confirm the in silico studies by showing that GLE inhibited NKA and SERCA activity in intact cells. In the present study, we also demonstrated the antiproliferative and anticancer effects of GLE in a variety of cancer cell lines with limited toxic effects on non-transformed cells. Moreover, our results revealed that known inhibitors of both NKA and SERCA pumps could also promote cell death in several cancer cell lines. In addition, a mouse xenograft cancer model showed GLE as able to reduce tumor size and progression. Finally, bioprofiling studies indicated a strong correlation between overexpression of both NKA and SERCA gene expression vs. survival rates. Overall, our results demonstrated that GLE can promote selective cancer cell death via inhibiting NKA and SERCA, and thus can be considered as a potential novel treatment for cancer. After molecular analysis of GLE by liquid chromatography-mass spectrometry and ESI-QTOF-MS analysis, it was found that the MS spectrum of the high abundant chromatographic peak purified sample highly consisted of annonacin.

Original languageEnglish
Article number764
JournalCell Death & Disease
Volume9
Issue7
ISSN2041-4889
DOIs
Publication statusPublished - 1 Jul 2018

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