Armelle T Mbaveng1, Godloves F Chi2, Idrios N Bonsou3, Sara Abdelfatah4, Alfred N Tamfu5, Elisabeth M O Yeboah6, Victor Kuete7, Thomas Efferth8. 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. Electronic address: armbatsa@yahoo.fr. 2. Department of Chemistry, Faculty of Science, University of Yaounde I, Yaounde, Cameroon. Electronic address: chigodloves@yahoo.com. 3. Department of Biochemistry, Faculty of Science, University of Dschang, Dschang, Cameroon. Electronic address: bonichrist89@yahoo.com. 4. Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: saabdelf@uni-mainz.de. 5. Chemical Engineering and Mineral Industries School, University of Ngaoundere, 454 Ngaoundere Cameroon. Electronic address: macntamfu@yahoo.co.uk. 6. Department of Chemistry, University of Botswana, Private Bag 0022, Gaborone, Botswana. Electronic address: emo.yeboah@gmail.com. 7. 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. Electronic address: kuetevictor@yahoo.fr. 8. 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
BACKGROUND: The discovery of novel phytochemicals represents a reasonable approach to fight malignancies, especially those which are resistant to standard chemotherapy. PURPOSE: We evaluated the cytotoxic potential of a naturally occurring N-acetylglycoside of oleanolic acid, aridanin, on 18 cancer cell lines, including sensitive and drug-resistant phenotypes mediated by P-glycoprotein, BCRP, p53 knockout, deletion-mutated EGFR, or BRAF mutations. Furthermore, metastasizing B16/F10 cells, HepG2 hepatocarcinoma and normal AML12 hepatocytes were investigated. The mechanisms of aridanin-induced cell death was further investigated. METHODS: The resazurin reduction assay (RRA) was applied to evaluate the cytotoxicity, autophagy, ferroptotic and necroptotic cell death. CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the caspase activities. Flow cytometry was applied for the analyses of cell cycle (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP; JC-1) and reactive oxygen species (ROS; H2DCFH-DA). RESULTS: Aridanin and doxorubicin (positive control) inhibited the proliferation of all cancer cell lines tested. The IC50 values for aridanin varied from 3.18 µM (CCRF-CEM cells) to 9.56 µM (HepG2 cells). Aridanin had considerably lower IC50 values than that of doxorubicin against multidrug-resistant CEM/ADR5000 cells and melanoma cell lines (MaMel-80a, Mel-2a, MV3, and SKMel-505). Aridanin induced apoptosis in CCRF-CEM cells through increase of ROS levels and MMP breakdown, and to a lesser extent via caspases activation. Aridanin also induced ferroptotic and necroptotic cell death. CONCLUSION: The present study opens good perpectives for the use of this phytochemical as an anticancer drug to combat multi-facorial resistance to established chemotherapeutics.
BACKGROUND: The discovery of novel phytochemicals represents a reasonable approach to fight malignancies, especially those which are resistant to standard chemotherapy. PURPOSE: We evaluated the cytotoxic potential of a naturally occurring N-acetylglycoside of oleanolic acid, aridanin, on 18 cancer cell lines, including sensitive and drug-resistant phenotypes mediated by P-glycoprotein, BCRP, p53 knockout, deletion-mutated EGFR, or BRAF mutations. Furthermore, metastasizing B16/F10 cells, HepG2 hepatocarcinoma and normal AML12 hepatocytes were investigated. The mechanisms of aridanin-induced cell death was further investigated. METHODS: The resazurin reduction assay (RRA) was applied to evaluate the cytotoxicity, autophagy, ferroptotic and necroptotic cell death. CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the caspase activities. Flow cytometry was applied for the analyses of cell cycle (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP; JC-1) and reactive oxygen species (ROS; H2DCFH-DA). RESULTS:Aridanin and doxorubicin (positive control) inhibited the proliferation of all cancer cell lines tested. The IC50 values for aridanin varied from 3.18 µM (CCRF-CEM cells) to 9.56 µM (HepG2 cells). Aridanin had considerably lower IC50 values than that of doxorubicin against multidrug-resistant CEM/ADR5000 cells and melanoma cell lines (MaMel-80a, Mel-2a, MV3, and SKMel-505). Aridanin induced apoptosis in CCRF-CEM cells through increase of ROS levels and MMP breakdown, and to a lesser extent via caspases activation. Aridanin also induced ferroptotic and necroptotic cell death. CONCLUSION: The present study opens good perpectives for the use of this phytochemical as an anticancer drug to combat multi-facorial resistance to established chemotherapeutics.
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: Gaëlle S Nguenang; Armelle T Mbaveng; Idrios N Bonsou; Godloves F Chi; Victor Kuete Journal: Evid Based Complement Alternat Med Date: 2022-03-29 Impact factor: 2.629