Phytomedicine. 2014 Oct 15;21(12):1525-33. doi: 10.1016/j.phymed.2014.07.011. Epub 2014 Aug 28.
Author information
- 1Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany.
- 2Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, Cameroon.
- 3Medicinal and Aromatic Plants Research Institute (MAPRI), National Centre for Research, Khartoum, Sudan.
- 4Abel Salazar Biomedical Sciences Institute, University of Porto, Portugal; Heidelberg School of Chinese Medicine, Heidelberg, Germany.
- 5Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Germany. Electronic address: efferth@uni-mainz.de.
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.
Copyright © 2014 Elsevier GmbH. All rights reserved.
Copyright © 2014 Elsevier GmbH. All rights reserved.
KEYWORDS:
ABC-transporter; Cluster analysis; Kinase inhibitor; Magnolia officinalis Honokiol; Microarrays; Multidrug resistance- PMID:
- 25442261
- [PubMed - indexed for MEDLINE]
