Victor Kuete1, Armelle T Mbaveng2, Maen Zeino3, Bathelemy Ngameni4, Gilbert Deccaux W F Kapche5, Simeon F Kouam5, Bonaventure T Ngadjui6, Thomas Efferth7. 1. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany ; Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon. 2. Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon. 3. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany. 4. Department of Pharmacognosy and Pharmaceutical Chemistry, Faculty of Medicine and Biomedical Sciences, University of Yaoundé I, Yaoundé, Cameroon. 5. Department of Chemistry, Higher Teachers' Training College, University of Yaoundé I, Yaoundé, Cameroon. 6. Department of Organic Chemistry, Faculty of Science, University of Yaoundé I, Yaoundé, Cameroon. 7. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany . Electronic address: efferth@uni-mainz.de.
Abstract
INTRODUCTION: The expression of diverse resistance mechanisms in cancer cells is one of the major barriers to successful cancer chemotherapy. METHODS: In the present study, we assessed the cytotoxicity of two naturally occurring flavonoids dorsmanin F (1, a flavanone) and poinsettifolin B (2, a chalcone) against 9 drug-sensitive and multidrug-resistant (MDR) cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analysed via flow cytometry. RESULTS: Compounds 1 and 2 displayed cytotoxic effects with IC50 values below 34 µM in all the 9 tested cancer cell lines. The IC50 values for flavanone 1 and chalcone 2 ranged from 5.34 µM and 1.94 µM (towards leukaemia CCRF-CEM cells) to 33.30 µM and 28.92 µM (towards MDA-MB-231-BCRP cells), respectively, and from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (against CEM/ADR5000 cells) for doxorubicin. The compounds induced apoptosis in CCRF-CEM leukaemia cells, mediated by MMP disruption and increased ROS production. CONCLUSIONS: Dorsmain F and poinsettifolin B are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers.
INTRODUCTION: The expression of diverse resistance mechanisms in cancer cells is one of the major barriers to successful cancer chemotherapy. METHODS: In the present study, we assessed the cytotoxicity of two naturally occurring flavonoidsdorsmanin F (1, a flavanone) and poinsettifolin B (2, a chalcone) against 9 drug-sensitive and multidrug-resistant (MDR) cancer cell lines. The resazurin reduction assay was used to evaluate the cytotoxicity of these compounds, whilst caspase-Glo assay was used to detect caspase activation. Cell cycle, mitochondrial membrane potential (MMP) and levels of reactive oxygen species (ROS) were all analysed via flow cytometry. RESULTS: Compounds 1 and 2 displayed cytotoxic effects with IC50 values below 34 µM in all the 9 tested cancer cell lines. The IC50 values for flavanone 1 and chalcone 2 ranged from 5.34 µM and 1.94 µM (towards leukaemia CCRF-CEM cells) to 33.30 µM and 28.92 µM (towards MDA-MB-231-BCRP cells), respectively, and from 0.20 µM (against CCRF-CEM cells) to 195.12 µM (against CEM/ADR5000 cells) for doxorubicin. The compounds induced apoptosis in CCRF-CEM leukaemia cells, mediated by MMP disruption and increased ROS production. CONCLUSIONS: Dorsmain F and poinsettifolin B are potential cytotoxic natural products that deserve more investigations to develop novel antineoplastic drugs against multifactorial drug-resistant cancers.