Triterpenoid saponins are specialised metabolites distributed widely in the plant kingdom that consist of one or more sugar moieties attached to triterpenoid aglycones. Despite the widely accepted view that glycosylation is catalysed by UDP-dependent glycosyltransferase (UGT), the UGT which catalyses the transfer of the conserved glucuronic acid moiety at the C-3 position of glycyrrhizin and various soyasaponins has not been determined. Here, we report that a cellulose synthase superfamily-derived glycosyltransferase (CSyGT) catalyses 3-O-glucuronosylation of triterpenoid aglycones. Gene co-expression analyses of three legume species (Glycyrrhiza uralensis, Glycine max, and Lotus japonicus) reveal the involvement of CSyGTs in saponin biosynthesis, and we characterise CSyGTs in vivo using Saccharomyces cerevisiae. CSyGT mutants of L. japonicus do not accumulate soyasaponin, but the ectopic expression of endoplasmic reticulum membrane–localised CSyGTs in a L. japonicus mutant background successfully complement soyasaponin biosynthesis. Finally, we produced glycyrrhizin de novo in yeast, paving the way for sustainable production of high-value saponins.

Multidrug resistance (MDR) is one of the most significant obstacles in cancer chemotherapy. One of the mechanisms involved in the development of MDR is the over-expression of P-glycoprotein (P-gp). It is widely known that natural compounds found in vegetables, fruits, plant-derived beverages and herbal dietary supplements not only have anticancer properties, but may also modulate P-gp activity. Therefore, the purpose of this investigation was to examine the effects of naturally occurring products on P-gp function in human breast cancer cell lines, MCF-7 (sensitive) and MCF-7/ADR (resistant). The accumulation of daunomycin (DNM), a P-gp substrate, was greater in the sensitive cells compared to the resistant cells, while the efflux of DNM was higher in the resistant cells compared to the sensitive cells over a period of 2 h. The IC50 value of DNM in the resistant cells was about 22 times higher than that in the sensitive cells, indicating an over-expression of P-gp in the resistant cells, MCF-7/ADR. All of the compounds tested, with the exception of fisetin, significantly decreased the IC50 value of DNM. Biochanin A showed the greatest increase in [3H]-DNM accumulation, increasing by 454.3 +/- 19.5% in the resistant cells, whereas verapamil, the positive control, increased the accumulation by 229.4 +/- 17.6%. Also, the accumulation of [3H]-DNM was increased substantially by quercetin and silymarin while it was reduced by fisetin. Moreover, biochanin A, silymarin, and naringenin significantly decreased DNM efflux from MCF-7/ADR cells compared with the control. These results suggest that some flavonoids such as biochanin A and silymarin may reverse MDR by inhibiting the P-gp function.

Five phenylbutenoid derivatives from the rhizomes of Zingiber cassumunar Roxb. (Zingiberaceae) were evaluated for their P-glycoprotein (P-gp) inhibitory effects in a P-gp over-expressing multidrug resistant (MDR) human breast cancer cell line, MCF-7/ADR. As a result, a phenylbutenoid dimer, (+/-)-trans-3-(3,4-dimethoxyphenyl)-4-[(E)-3,4-dimethoxystyryl]cyclohex-1-ene (1), exhibited highly potent P-gp inhibitory activity, decreasing the IC(50) value of daunomycin (DNM) to 4.31 +/- 0.40 microm in the cells (DNM IC(50) = 37.1 +/- 0.59 microm). The positive control, verapamil decreased the IC(50) value of DNM to 6.94 +/- 0.40 microm. Three phenylbutenoid monomers, 2-4 from this plant, also resulted in a significant decrease in the IC(50) values of DNM compared with the control. In particular, compound 1 markedly enhanced [(3)H]-DNM accumulation and significantly reduced [(3)H]-DNM efflux compared with the control, and this effect was more potent than that of verapamil, a well-known P-gp inhibitor. These results suggest that compound 1 of Z. cassumunar can be developed as a potent chemo-sensitizing agent that reverses P-gp-mediated MDR in human cancer chemotherapy.

This study examined the effects of the kaempferol derivatives extracted from Zingiber zerumbet on the accumulation and efflux of [(3)H]-daunomycin (DNM) in P-glycoprotein (P-gp) overexpressing multidrug resistant (MDR) human breast cancer cells, MCF-7/ADR. Of six kaempferol derivatives extracted from Z. zerumbet, kaempferol-3-O-methyl ether (1) and kaempferol-3,4'-O-dimethyl ether (2) showed a potent P-gp inhibitory effect as great as verapamil, a well-known P-gp inhibitor. The P-gp inhibitory activity of these two compounds was through a 3-fold increase of the level of [(3)H]-DNM accumulation and a decrease of P-gp-mediated efflux. These results suggest that the kaempferol derivative components of Z. zerumbet can be used as a scaffold for developing agents that reverse P-gp-mediated MDR in human cancer chemotherapy.

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