Bioassay-guided fractionation of the MeOH extract of Thuja orientalis fruits using a DPPH (2,2-diphenyl-1-picrylhydrazyl) assay led to the isolation of 9 flavonoids: cupressuflavone (1), amentoflavone (2), robustaflavone (3), afzelin (4), (+)-catechin (5), quercitrin (6), hypolaetin 7-O-beta-xylopyranoside (7), isoquercitrin (8) and myricitrin (9). Their chemical structures were determined by spectroscopic analyses. The free radical scavenging and human neutrophil elastase (HNE) inhibitory activities were evaluated for the isolated compounds. By DPPH scavenging assay, compounds 5, 6, 7, 8 and 9 showed anti-oxidant activities with IC(50) values of 28.66, 31.19, 18.30, 26.63 and 15.10 microM, respectively. By ABTS [2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt] scavenging assay, these compounds also exhibited potent anti-oxidant activities with IC(50) values of 6.77, 13.96, 6.97, 22.79 and 9.96 microM, respectively. Of note, compounds 1, 2 and 3 showed significant HNE inhibitory activities with IC(50) values of 8.09, 1.27 and 1.33 microM, respectively.

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Glucose deprivation, a pathophysiological cell condition, causes up-regulation of GRP78 and induction of etoposide resistance in human cancer cells. The induction of drug resistance can be partly explained by the fact that GRP78 can block activation of caspase-7 induced by treatment with etoposide. Therefore, downregulating GRP78 expression may be a novel strategy anticancer drug development. Based on that premise, we established a screening program for anticancer agents that exhibit preferential cytotoxic activity for etoposide-resistant cancer cells under glucose-deprived conditions. We recently isolated an active compound, AR-054, from the culture broth of Streptomyces sp., which prevents stress-induced etoposide resistance in vitro. AR-054 was identified as piericidin A, a prototypical compound, by ESI-MS analysis and various NMR spectroscopic methods. Here, we showed that piericidin A suppressed the accumulation of GRP78 protein and was also highly toxic to etoposide-resistant HT-29 cells, with IC50 values for colony formation of 6.4 and 7.7 nM under 2-deoxyglucose supplemented and glucose-deprived conditions, respectively. Interestingly, piericidin A had no effect under normal growth conditions. Therefore, we suggest that piericidin A prevents up-regulation of GRP78, and exhibits cytotoxicity in glucose-deprived HT-29 cells that are resistant to etoposide.

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