Pharmacogenomics of Scopoletin in Tumor Cells.
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.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz, Germany. seo@uni-mainz.de.
Ean-Jeong
EJ
Seo
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz, Germany. saeedm@uni-mainz.de.
Mohamed
M
Saeed
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China. klaw@must.edu.mo.
Betty Yuen Kwan
BY
Law
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China. wag1114@foxmail.com.
An Guo
AG
Wu
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz, Germany. kadioglu@uni-mainz.de.
Onat
O
Kadioglu
Abel Salazar Biomedical Sciences Institute, University of Porto, Porto 4099-002, Portugal. heidelbergschool@aol.com.|Heidelberg School of Chinese Medicine, Heidelberg 69126, Germany. heidelbergschool@aol.com.
Henry Johannes
HJ
Greten
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Mainz, Staudinger Weg 5, 55128 Mainz, Germany. efferth@uni-mainz.de.
Thomas
T
Efferth
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics; D019306:Artemisia / Q000737:chemistry; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010597:Pharmacogenetics; D010936:Plant Extracts / Q000008:administration & dosage* / Q000737:chemistry; D040081:Protein Array Analysis; D012603:Scopoletin / Q000008:administration & dosage* / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000096:biosynthesis
D018528:ATP-Binding Cassette Transporters; D016328:NF-kappa B; D010936:Plant Extracts; C498143:RELA protein, human; D051996:Transcription Factor RelA; D012603:Scopoletin
ABC-transporter; cluster analysis; coumarin; herbal medicine; microarrays; multidrug resistance; phytotherapy