Molecular biology of cantharidin in cancer cells

Abstract

Herbal medicine is one of the forms of traditional medical practice. Traditional Chinese medicine (TCM) and traditional Vietnamese medicine (TVM) are well-known for their long-standing tradition of herbal medicine. Secreted by many species of blister beetle, most notably by the 'Spanish fly' (Lytta vesicatoria), cantharidin inhibits protein phosphatases 1 and 2A (PP1, PP2A). Blister beetle has been used in Asian traditional medicine to treat Molluscum contagiosum virus (MCV) infections and associated warts, and is now also used for cancer treatment. A combination of both genomic and postgenomic techniques was used in our studies to identify candidate genes affecting sensitivity or resistance to cantharidin. Cantharidin was not found to be related to multidrug resistance phenotype, suggesting its potential usefulness for the treatment of refractory tumors. Oxidative stress response genes diminish the activity of cantharidin by inducing DNA strand breaks which may be subject to base excision repair and induce apoptosis in a p53- and Bcl2-dependent manner. Cantharidin is one of many natural products used in traditional Chinese medicine and traditional Vietnamese medicine for cancer treatment. Combined methods of pharmaceutical biology and molecular biology can help elucidate modes of action of these natural products.

Figure 1

Medicinal plants and animals used in Vietnamese medicine and cytotoxicity of hexane, water or methanol extracts (10 μg/ml) to CCRF-CEM leukemia cells. (1) Lytta vesicatoria (whole beetles), (2) Pueralia lobata (roots), (3) Momordica charantia (roots, branches), (4) Momordica charantia (fruits), (5) Dichroa febrifuga (roots), (6) Panax ginseng C.A.Mey., (7) Curcuma longa (rhizoma), (8) Trichosanthes kirilowii Maxim (kernels), (9) Glycyrrhiza uralensis (roots). Growth inhibitory activity was measured using a growth inhibition assay [16].

Figure 2

Dendrograms and cluster image map obtained by hierarchical cluster analysis (complete linkage method) of mRNA expression of 21 genes in 60 NCI cell lines. The genes are published [10]. The dendrogram on the right shows the clustering of cell lines and the dendrogram on the top shows clustering of genes. The cluster image map corresponds to each mRNA expression value obtained by microarray analysis. The expression values have been normalized and color-coded as indicated. The figure is taken from [10].