title: Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and molecular docking.
abstract: A main problem in oncology is the development of drug-resistance. Some plant-derived lignans are established in cancer therapy, e.g. the semisynthetic epipodophyllotoxins etoposide and teniposide. Their activity is, unfortunately, hampered by the ATP-binding cassette (ABC) efflux transporter, P-glycoprotein. Here, we investigated the bisphenolic honokiol derived from Magnolia officinalis. P-glycoprotein-overexpressing CEM/ADR5000 cells were not cross-resistant to honokiol, but MDA-MB-231 BRCP cells transfected with another ABC-transporter, BCRP, revealed 3-fold resistance. Further drug resistance mechanisms analyzed study was the tumor suppressor TP53 and the epidermal growth factor receptor (EGFR). HCT116 p53(-/-) did not reveal resistance to honokiol, and EGFR-transfected U87.MG EGFR cells were collateral sensitive compared to wild-type cells (degree of resistance: 0.34). To gain insight into possible modes of collateral sensitivity, we performed in silico molecular docking studies of honokiol to EGFR and EGFR-related downstream signal proteins. Honokiol bound with comparable binding energies to EGFR (-7.30 ± 0.01 kcal/mol) as the control drugs erlotinib (-7.50 ± 0.30 kcal/mol) and gefitinib (-8.30 ± 0.10 kcal/mol). Similar binding affinities of AKT, MEK1, MEK2, STAT3 and mTOR were calculated for honokiol (range from -9.0 ± 0.01 to 7.40 ± 0.01 kcal/mol) compared to corresponding control inhibitor compounds for these signal transducers. This indicates that collateral sensitivity of EGFR-transfectant cells towards honokiol may be due to binding to EGFR and downstream signal transducers. COMPARE and hierarchical cluster analyses of microarray-based transcriptomic mRNA expression data of 59 tumor cell lines revealed a specific gene expression profile predicting sensitivity or resistance towards honokiol.
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Saeed
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon.
authors.forename: Victor
authors.initials: V
authors.lastname: Kuete
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Onat
authors.initials: O
authors.lastname: Kadioglu
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Börtzler
authors.affiliation: Medicinal and Aromatic Plants Research Institute (MAPRI), National Centre for Research, Khartoum, Sudan.
authors.forename: Hassan
authors.initials: H
authors.lastname: Khalid
authors.affiliation: Abel Salazar Biomedical Sciences Institute, University of Porto, Portugal; Heidelberg School of Chinese Medicine, Heidelberg, Germany.
authors.forename: Henry Johannes
authors.initials: HJ
authors.lastname: Greten
authors.affiliation: Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: efferth@uni-mainz.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Efferth
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D031566:Magnolia / Q000737:chemistry*; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D015398:Signal Transduction / Q000187:drug effects; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D000498:Allyl Compounds; D010636:Phenols
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D001713:Biphenyl Compounds; D066246:ErbB Receptors; D017705:Lignans; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C495901:TP53 protein, human; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols; C512478:EGFR protein, human
keywords: ABC-transporter; Cluster analysis; Kinase inhibitor; Magnolia officinalis Honokiol; Microarrays; Multidrug resistance