Pharmacogenomics of cantharidin in tumor cells.
Cantharis vesicatoria (blister beetle) is used in Chinese medicine and has been categorized as highly toxic in the Chinese pharmacopeia. In Europe, Cantharis patches have been used since ages to treat various skin-related diseases. We investigated the cytotoxicity of the Cantharis ingredient, cantharidin, in 41 tumor cell lines (Oncotest panel) and compared the results with those of 60 cell lines of the National Cancer Institute, USA. We found profound activity at low micromolar concentrations (log ₁₀IC₅₀ values between -6.980 and 5.009 M). Cantharidin bound to protein phosphatase 2A (PP2A) with higher affinity (-8.12 kcal/mol) than to PP1 (-6.25 kcal/mol) in molecular docking analyses. Using a PCR array for 84 apoptosis genes, cantharidin treatment upregulated gene expression of caspase-1 and nerve growth factor receptor, but downregulated mRNA expression of Bcl-2 like protein 10, Fas ligand, and tumor necrosis factor-α. By using COMPARE analysis of microarray-based transcriptome-wide mRNA expressions, 21 genes were found to significantly correlate with response of 60 tumor cell lines to cantharidin. As shown by hierarchical cluster analysis and chi-squared test, the distribution of cell lines in the dendrogram according to their gene expression profiles predicted sensitivity or resistance to cantharidin (P=6.482 × 10(-5)). The compassionate use of Cantharis patches in two patients suffering from basalioma and Mycosis fungoides, respectively, considerably improved the diseases without signs of toxicity. In conclusion, these results indicate that cantharidin may be a useful candidate to develop novel strategies for cancer therapy.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Onat
O
Kadioglu
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Navid Salehi
NS
Kermani
Oncotest GmbH, Institute of Experimental Oncology, Freiburg, Germany.
Gerhard
G
Kelter
Department of Anatomy and Experimental Morphology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Udo
U
Schumacher
Oncotest GmbH, Institute of Experimental Oncology, Freiburg, Germany.
Heinz-Herbert
HH
Fiebig
Abel Salazar Biomedical Sciences Institute, University of Porto, Portugal; Heidelberg School of Chinese Medicine, Heidelberg, Germany.
Henry Johannes
HJ
Greten
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
Thomas
T
Efferth
D000818:Animals; D001665:Binding Sites; D002193:Cantharidin / Q000378:metabolism / Q000633:toxicity*; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D020411:Oligonucleotide Array Sequence Analysis; D010597:Pharmacogenetics; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017476:Receptors, Neuropeptide Y / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D017476:Receptors, Neuropeptide Y; D002193:Cantharidin
Blister beetle; Cancer; Cantharidin; Microarray; Protein phosphatase