A naturally occuring triterpene saponin ardisiacrispin B displayed cytotoxic effects in multi-factorial drug resistant cancer cells via ferroptotic and apoptotic cell death

  • Phytomedicine. 2018 Apr 1;43:78-85. doi: 10.1016/j.phymed.2018.03.035.
Armelle T Mbaveng  1 ,  Blanche L Ndontsa  2 ,  Victor Kuete  1 ,  Yves M M Nguekeu  2 ,  İlhami Çelik  3 ,  Roukayatou Mbouangouere  2 ,  Pierre Tane  2 ,  Thomas Efferth  4
Affiliations
  • 1. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, Mainz 55128, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon.
  • 2. Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Cameroon.
  • 3. Department of Chemistry, Faculty of Science, Anadolu University, Tepebaşı, Eskisehir 26470, Turkey.
  • 4. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, Mainz 55128, Germany. Electronic address: [email protected].
PMID: 29747757 DOI: 10.1016/j.phymed.2018.03.035
Abstract

Introduction: Multidrug resistance of Cancer cells constitutes a serious problem in chemotherapy and a challenging issue in the discovery of new cytotoxic drugs. Many saponins are known to display anti-cancer effects. In this study, the cytotoxicity and the modes of action of a naturally occuring oleanane-type tritepene saponin, ardisiacrispin B isolated from the fruit of Ardisia kivuensis Taton (Myrsinaceae) was evaluated on a panel of 9 Cancer cell lines including various sensitive and drug-resistant phenotypes.

Methods: Resazurin reduction assay was used to evaluate cytotoxicity and ferroptotic cell death of samples; caspase-Glo assay was used to detect the activation of caspases in CCRF-CEM leukemia cells. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells by annexin V/PI staining, analysis of mitochondrial membrane potential (MMP) and measurement of Reactive Oxygen Species (ROS).

Results: Ardisiacrispin B displayed significant cytotoxic effects in the 9 tested Cancer cell lines with IC50 values below 10 µM. The IC50 values ranges were 1.20 µM (towards leukemia CCRF-CEM cells) to 6.76 µM [against heptocarcinoma HepG2 cells] for ardisiacrispin B and 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against resistant CEM/ADR5000 leukemia cells) for doxorubicin. Collateral sensitivity of resistant HCT116p53-/- colon adenocarcinoma cells to ardisiacripsin B was observed. Ardisiacrispin B induced Apoptosis in CCRF-CEM cells via activation of inititator caspases 8 and 9 and effector Caspase 3/7, alteration of MMP and increase in ROS production. Ferroptosis also contributed to the cytotoxicity of ardisiacrispin B.

Conclusions: The studied oleanane-type triterpene saponin is a good cytotoxic molecule that deserve more detailed exploration in the future, to develop novel cytotoxic drugs to combat both sensitive and drug-resistant cancers.

Keywords
Ardisiacrispin B; Cell cycle distribution; Cytotoxicity; Ferroptosis; Mitochondrial membrane potential; Saponin.
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