Superiority of flavonol 2,3-dehydrosilybin than its parental silybin in inhibiting DNA topoisomerase I: An anti-cancer mechanism of 2,3-dehydrosilybin

Antioxidant silybin is the major compound found in silymarin extracts which have been used to treat liver diseases for several decades. Silybin is now being tested in clinical trials to treat prostate and breast cancers. We have previously reported that the oxidized form of silybin so-called 2,3-dehydrosilybin (DHS) exhibits more potent antioxidant activities than silybin by three folds in in vitro and in vivo systems. Compared with silybin, DHS was more cytotoxic and capable of inhibiting releases of metalloproteinase-2,-9 by five folds [BBA 1780(5): 837, 2008]. In addition, we have shown that DHS (but not silybin) was capable of sensitizing TNF-α–induced apoptosis [Chemotherapy 54(1): 23, 2008]. We hypothsized that DHS may inhibit enzymes that regulate transcription such as topoisomerases (topo). Here we utilized model FIB and EPI cell lines exhibiting different levels of malignancies [Oncogene 22(38): 6045, 2003]. After 24h treatment of more transformed FIB cells, 30µM DHS induced apoptosis measured by mitochondrial membrane potential disruption and DNA fragmentation. We demonstrated that treatment of FIB cells with 30µM DHS for 24h produced significant decreases of extractable topo I activity while treatment with 30µM silybin did not have any effects. Less transformed EPI cells were more resistant against 30µM DHS-induced topo I inhibition. This indicates DHS selectivity towards cancer phenotype. Inhibitory effects of 10–50µM DHS of specific Topo I activity were also found in cell-free assays using purified topo I, while 50–100µM silybin did not have any effects. Silybin at 100µM however could inhibit topo I activity prepared from nuclear extracts. Being superior to silybin, DHS induced apoptotic DNA fragmentation which was associated with topo I inhibition. Taken together, DHS may serve as a chemotherapeutic agent by targeting mitochondria and DNA topo I and with its enhanced sensitization potency and selectivity towards cancer phenotype.

anti-cancer - antioxidants - flavonoids - topoisomerase