Molecules. 2016 Apr 15;21(4). pii: E496. doi: 10.3390/molecules21040496.
- 1Department
of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry,
Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz,
Germany. seo@uni-mainz.de.
- 2Department of
Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes
Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
saeedm@uni-mainz.de.
- 3State Key Laboratory of Quality
Research in Chinese Medicine, Macau University of Science and
Technology, Macau, China. klaw@must.edu.mo.
- 4State
Key Laboratory of Quality Research in Chinese Medicine, Macau University
of Science and Technology, Macau, China. wag1114@foxmail.com.
- 5Department
of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry,
Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz,
Germany. kadioglu@uni-mainz.de.
- 6Abel Salazar Biomedical Sciences Institute, University of Porto, Porto 4099-002, Portugal. heidelbergschool@aol.com.
- 7Heidelberg School of Chinese Medicine, Heidelberg 69126, Germany. heidelbergschool@aol.com.
- 8Department
of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry,
Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz,
Germany. efferth@uni-mainz.de.
Abstract
Drug
resistance and the severe side effects of chemotherapy necessitate the
development of novel anticancer drugs. Natural products are a valuable
source for drug development. Scopoletin is a coumarin compound, which
can be found in several Artemisia species and other plant genera.
Microarray-based RNA expression profiling of the NCI cell line panel
showed that cellular response of scopoletin did not correlate to the
expression of ATP-binding cassette (ABC) transporters as classical drug
resistance mechanisms (ABCB1, ABCB5, ABCC1, ABCG2). This was also true
for the expression of the oncogene EGFR and the mutational status of the
tumor suppressor gene, TP53. However, mutations in the RAS oncogenes
and the slow proliferative activity in terms of cell doubling times
significantly correlated with scopoletin resistance. COMPARE and
hierarchical cluster analyses of transcriptome-wide mRNA expression
resulted in a set of 40 genes, which all harbored binding motifs in
their promoter sequences for the transcription factor, NF-κB, which is
known to be associated with drug resistance. RAS mutations, slow
proliferative activity, and NF-κB may hamper its effectiveness. By in
silico molecular docking studies, we found that scopoletin bound to
NF-κB and its regulator IκB. Scopoletin activated NF-κB in a SEAP-driven
NF-κB reporter cell line, indicating that NF-κB might be a resistance
factor for scopoletin. In conclusion, scopoletin might serve as lead
compound for drug development because of its favorable activity against
tumor cells with ABC-transporter expression, although NF-κB activation
may be considered as resistance factor for this compound. Further
investigations are warranted to explore the full therapeutic potential
of this natural product.
KEYWORDS:
ABC-transporter; cluster analysis; coumarin; herbal medicine; microarrays; multidrug resistance; phytotherapy
- PMID:
- 27092478
- [PubMed - in process]
-
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