No abstract

We used the whole genome approach to identify major functional categories of genes whose expression depends on gestational age. Using microarray analysis, we compared gene expression profiles in the villous tissues of 1 st (45-59 days) and 2 nd trimester (109-115 days) placentae versus C-section term placentae. We found that in 1 st trimester placentae, genes related to cell cycle, DNA, amino acids, and carbohydrate metabolism were significantly overrepresented, while genes related to signal transduction were underrepresented. Among genes involved in organism defense, we identified genes involved in chemical response, metabolism, and transport. Analysis of signal transduction pathways suggested, and subsequently confirmed independently, that the Wnt pathway was changed with gestational age leading to inhibition of β-catenin protein expression. Our study will serve as a reference database to gain insight into the regulation of gene expression in the developing placentae and to compare with gene expression in placentae from complicated pregnancies.

We studied the effects of tea catechins, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG) on the P-glycoprotein (P-gp) function in multidrug-resistant P-gp over-expressing KB-C2 cells. EC did not have any effects on cellular accumulation of P-gp substrates, rhodamine-123 and daunorubicin, but the other catechins increased the accumulation in the order of EGC < ECG < EGCG. The effects of EGCG were larger than those of verapamil and quercetin. Since these catechins inhibited the efflux of P-gp substrates, the elevation of substrate accumulation seemed to be induced by the inhibition of the efflux transporter. The results showed that the inhibitory effects of the catechins did not depend on their total hydrophobicity, but significantly depended on their chemical structure. The presence of the galloyl moiety on the C-ring markedly increased the n-octanol/PBS partition coefficients of the catechins and their activity on P-gp. On the other hand, the presence of the trihydric pyrogallol group as the B-ring decreased the partition coefficients but increased the activity on P-gp, compared with the action of the corresponding catechins with a dihydric catechol B-ring.

These results suggest that dietary phytochemicals, such as glycyrrhetinic acid found in licorice, have dual inhibitory effects on P-glycoprotein and MRP1 and might become useful to enhance the efficacy of cancer chemotherapy.

Overexpression of P-glycoprotein (P-gp), a plasma membrane transporter which extrudes chemotherapeutic agents out of cells, has been associated with the multidrug resistance of cancer cells. Compounds such as verapamil, dihydropyridine analogs, quinidine and cyclosporin A reversed this P-gp-mediated multidrug resistance (MDR) due to their inhibition of transporter activity. 1,2) In addition to these compounds, it has been revealed that flavonoids and other polyphenols modulate P-gp activity. [3][4][5][6] Although the structure-activity relationships of flavonoids on P-gp functions have been studied, 5,7,8) they are still not clear, especially concerning their effects in whole cells. Recently, we revealed that tea catechins inhibited P-gp function dependent on their chemical structure in multidrug-resistant human epidermal carcinoma cell line KB-C2 cells, 9) which overexpress P-gp. 10)Among the tea catechins, we found the maximum activity in the (Ϫ)epigallocatechin gallate whose chemical structure is shown in Fig. 1. We clarified that the presence of the galloyl moiety in the C ring, and the presence of the trihydric pyrogallol group as the B ring instead of the dihydric catechol group, markedly increased its activity on P-gp, although their effects on the partition coefficients between n-octanol and phosphate-buffered saline (PBS) were opposite to each other. 9)In this study, we examined the structure-activity relationships of seven flavonoids, naringenin (flavanone), baicalein (flavone), kaempferol, quercetin, myricetin, morin, and fisetin (flavonols) (Fig. 1), which do not have large substituents like the galloyl group, as well as two glycosides of quercetin, for their effects on P-gp-mediated drug extrusion in KB-C2 cells. We analyzed the effects from the standpoints of chemical structure, conformation and hydrophobicity. We studied the importance of the 2,3-double bond in the C ring, in relation to the stereoscopic structure of flavonoids. Furthermore, we studied the effects of hydrophobicity of the flavonoids on the inhibitory activity to P-gp function. For this study, we used fluorescent rhodamine-123 and daunorubicin as the P-gp substrates; these substrates have often been used for the study of various P-gp transport modulators including flavonoids.3,6,11) Although daunorubicin has also been revealed to be a substrate of multidrug resistance-associated protein 1 (MRP1), 12) since MRP1 is rarely found in KB-C2 cells, 13) its involvement in substrate efflux is negligible. We studied the effects of flavonoids, naringenin (flavanone), baicalein (flavone), kaempferol, quercetin, myricetin, morin, and fisetin (flavonols) as well as two glycosides of quercetin on P-glycoprotein (P-gp) function in multidrug-resistant P-gp overexpressing KB-C2 cells. Flavonoids such as kaempferol and quercetin increased the accumulation of rhodamine-123 dependent on their chemical structure. Analysis by flow cytometry indicated that the increase in substrate accumulation was due to the inhibition of substrate efflux. Naringenin, w...

Multidrug resistance is a phenomenon whereby tumors become resistant to structurally unrelated anticancer drugs. P-glycoprotein belongs to the large ATP-binding cassette (ABC) transporter superfamily of membrane transport proteins. P-glycoprotein mediates resistance to various classes of anticancer drugs including vinblastine, daunorubicin, and paclitaxel, by actively extruding the drugs from the cells. The quest for inhibitors of anticancer drug efflux transporters has uncovered natural compounds, including (-)-epigallocatechin gallate, curcumin, capsaicin, and guggulsterone, as promising candidates. In this review, studies on the effects of natural compounds on P-glycoprotein and anticancer drug efflux transporters are summarized.

No abstract

No abstract