Fozia A Adem1, Armelle T Mbaveng2, Victor Kuete3, Matthias Heydenreich4, Albert Ndakala5, Beatrice Irungu6, Abiy Yenesew7, Thomas Efferth8. 1. Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya; Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany. Electronic address: fozuti@yahoo.com. 2. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon. Electronic address: armbatsa@yahoo.fr. 3. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon. Electronic address: kuetevictor@yahoo.fr. 4. Institute of Chemistry, University of Potsdam, P.O. Box 60 15 53, D-14415 Potsdam, Germany. Electronic address: mheydenr@uni-potsdam.de. 5. Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya. Electronic address: andakala@uonbi.ac.ke. 6. Centre for Traditional Medicine and Drug Research, Kenya Medical Research Institute, P.O. Box 54840-00200, Nairobi, Kenya. Electronic address: birungu18@gmail.com. 7. Department of Chemistry, University of Nairobi, P.O. Box 30197-00100, Nairobi, Kenya. Electronic address: ayenesew@uonbi.ac.ke. 8. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Stawdenger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
Abstract
BACKGROUND: While incidences of cancer are continuously increasing, drug resistance of malignant cells is observed towards almost all pharmaceuticals. Several isoflavonoids and flavonoids are known for their cytotoxicity towards various cancer cells. PURPOSE: The aim of this study was to determine the cytotoxicity of isoflavones: osajin (1), 5,7-dihydroxy-4'-methoxy-6,8-diprenylisoflavone (2) and biflavonoids: chamaejasmin (3), 7,7″-di-O-methylchamaejasmin (4) and campylospermone A (5), a dimeric chromene [diphysin(6)] and an ester of ferullic acid with long alkyl chain [erythrinasinate (7)] isolated from the stem bark and roots of the Kenyan medicinal plant, Ormocarpum kirkii. The mode of action of compounds 2 and 4 was further investigated. METHODS: The cytotoxicity of compounds was determined based on the resazurin reduction assay. Caspases activation was evaluated using the caspase-Glo assay. Flow cytometry was used to analyze the cell cycle (propodium iodide (PI) staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). CCRF-CEM leukemia cells were used as model cells for mechanistic studies. RESULTS: Compounds 1, 2 and 4 displayed IC50 values below 20 µM towards CCRF-CEM and CEM/ADR5000 leukemia cells, and were further tested towards a panel of 7 carcinoma cells. The IC50 values of the compounds against carcinoma cells varied from 16.90 µM (in resistant U87MG.ΔEGFR glioblastoma cells) to 48.67 µM (against HepG2 hepatocarcinoma cells) for 1, from 7.85 µM (in U87MG.ΔEGFR cells) to 14.44 µM (in resistant MDA-MB231/BCRP breast adenocarcinoma cells) for 2, from 4.96 µM (towards U87MG.ΔEGFRcells) to 7.76 µM (against MDA-MB231/BCRP cells) for 4, and from 0.07 µM (against MDA-MB231 cells) to 2.15 µM (against HepG2 cells) for doxorubicin. Compounds 2 and 4 induced apoptosis in CCRF-CEM cells mediated by MMP alteration and increased ROS production. CONCLUSION: The present report indicates that isoflavones and biflavonoids from Ormocarpum kirkii are cytotoxic compounds with the potential of being exploited in cancer chemotherapy. Compounds 2 and 4 deserve further studies to develop new anticancer drugs to fight sensitive and resistant cancer cell lines.
BACKGROUND: While incidences of cancer are continuously increasing, drug resistance of malignant cells is observed towards almost all pharmaceuticals. Several isoflavonoids and flavonoids are known for their cytotoxicity towards various cancer cells. PURPOSE: The aim of this study was to determine the cytotoxicity of isoflavones: osajin (1), 5,7-dihydroxy-4'-methoxy-6,8-diprenylisoflavone (2) and biflavonoids: chamaejasmin (3), 7,7″-di-O-methylchamaejasmin (4) and campylospermone A (5), a dimeric chromene [diphysin(6)] and an ester of ferullic acid with long alkyl chain [erythrinasinate (7)] isolated from the stem bark and roots of the Kenyan medicinal plant, Ormocarpum kirkii. The mode of action of compounds 2 and 4 was further investigated. METHODS: The cytotoxicity of compounds was determined based on the resazurin reduction assay. Caspases activation was evaluated using the caspase-Glo assay. Flow cytometry was used to analyze the cell cycle (propodium iodide (PI) staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). CCRF-CEM leukemia cells were used as model cells for mechanistic studies. RESULTS: Compounds 1, 2 and 4 displayed IC50 values below 20 µM towards CCRF-CEM and CEM/ADR5000 leukemia cells, and were further tested towards a panel of 7 carcinoma cells. The IC50 values of the compounds against carcinoma cells varied from 16.90 µM (in resistant U87MG.ΔEGFR glioblastoma cells) to 48.67 µM (against HepG2 hepatocarcinoma cells) for 1, from 7.85 µM (in U87MG.ΔEGFR cells) to 14.44 µM (in resistant MDA-MB231/BCRP breast adenocarcinoma cells) for 2, from 4.96 µM (towards U87MG.ΔEGFRcells) to 7.76 µM (against MDA-MB231/BCRP cells) for 4, and from 0.07 µM (against MDA-MB231 cells) to 2.15 µM (against HepG2 cells) for doxorubicin. Compounds 2 and 4 induced apoptosis in CCRF-CEM cells mediated by MMP alteration and increased ROS production. CONCLUSION: The present report indicates that isoflavones and biflavonoids from Ormocarpum kirkii are cytotoxic compounds with the potential of being exploited in cancer chemotherapy. Compounds 2 and 4 deserve further studies to develop new anticancer drugs to fight sensitive and resistant cancer cell lines.
Authors: Idrios N Bonsou; Armelle T Mbaveng; Gaëlle S Nguenang; Godloves F Chi; Victor Kuete; Thomas Efferth Journal: BMC Complement Med Ther Date: 2022-07-04
Authors: Carolina A de Lima; Mayra C Z Cubero; Yollanda E M Franco; Carla D P Rodrigues; Jessyane R do Nascimento; Débora B Vendramini-Costa; Juliana M Sciani; Cláudia Q da Rocha; Giovanna B Longato Journal: Biomed Res Int Date: 2022-02-11 Impact factor: 3.411