A new benzoquinone and a new stilbenoid from Paphiopedilum exul (Ridl.) Rolfe.

One new alkyl benzoquinone, paphionone (1), one new trans-stilbenoid, (E)-6,5'-dihydroxy-2,3'-dimethoxystilbene (2), and eight known stilbenoids and flavonoids (3-10) were isolated from the leaves and roots of Paphiopedilum exul (Orchidaceae). Their chemical structures were determined based on IR, ECD, MS and NMR analyses. Cytotoxicity of all isolated compounds towards human hepatocellular carcinoma (HepG2) cell line was examined in vitro by MTT assay. The para-hydroxybenzyl substituted stilbene 10 was potently cytotoxic to the cancer cells, with an IC50 value of 4.80 ± 1.10 µM (selectivity index = 20.83). All compounds were non-toxic to normal human embryo fibroblast (OUMS-36) cell line.

Anticancer and chemosensitizing activities of stilbenoids from three orchid species.

Recently, we have isolated and identified several bioactive flavonoids and stilbenoids with potential anticancer activity from Thai orchids. In this study, we further investigated the cytotoxic and chemosensitizing activities of these phytochemicals (namely, pinocembrin, cardamonin, isalpinin, galangin, pinosylvin monomethyl ether, 2,3'-dihydroxy-5'-methoxystilbene, (E)-2,5'-dihydroxy-2'-(4-hydroxybenzyl)-3'-methoxystilbene, 2,3-dihydroxy-3',5'-dimethoxystilbene, 2,3'-dihydroxy-5,5'-dimethoxystilbene, 3,4'-dihydroxy-5-methoxystilbene and batatasin III) against breast cancer MCF7 cells and its two multidrug resistant (MDR) sublines (MCF7/DOX and MCF7/MX). Cytotoxicity was determined with MTT assay for the estimation of the half maximal cytotoxic concentrations (IC50). Effects of the test compounds on activities of efflux transporters (BCRP, P-gp, MRP1, and MRP2) were evaluated with substrate accumulation assays using fluorometry and flow cytometry analysis. Out of these 11 test compounds, the stilbene pinosylvin monomethyl ether displayed its cytotoxicity specifically toward MCF7 cells (IC50 = 6.2 ± 1.2 µM, 72-h incubation) with 4.96 folds higher than normal fibroblast. Its potency decreased in MCF7/DOX and MCF7/MX cells by 3.94 and 7.38 folds, respectively. Our transporter assay indicated that this stilbene significantly reduced the activities of P-gp, MRP1, and MRP2, but not BCRP. After 48-h co-incubation, this stilbene (at 2 µM) synergistically increased doxorubicin- and mitoxantrone-mediated cytotoxicity in MCF7, MCF7/DOX, and MCF7/MX cells potentially by increasing the intracellular level of cytotoxic drug. Pinosylvin monomethyl ether could sensitize breast cancer cells to chemotherapy and overcome MDR, in part, via the inhibition of drug efflux transporters.

Three new cytotoxic stilbene dimers from paphiopedilum dianthum.

Three new stilbene dimers, paphiodianthins A-C (1-3), and nine known stilbenes, lignan and flavonoids (4-12) were isolated from the roots and leaves of Paphiopedilum dianthum (Orchidaceae). The structures of new compounds were elucidated from their NMR, HRESIMS and IR spectroscopic data. Cytotoxic activity of all isolated compounds was evaluated by in vitro MTT assay against two human cancer cell lines (MCF-7, Caco-2), doxorubicin-resistant and mitoxantrone-resistant MCF-7 sublines, as well as a normal cell line (NIH/3T3). Stilbenes 1, 3, 10 and 11 were strongly cytotoxic to both cancer cell lines with IC50 values ranging from 0.50 to 4.51 µM. Compounds 1, 10 and 11 were also active against chemotherapy-resistant MCF-7 sublines.

N-Trans-p-Coumaroyltyramine Enhances Indomethacin- and Diclofenac-induced Apoptosis Through Endoplasmic Reticulum Stress-dependent Mechanism in MCF-7 Cells.

BACKGROUND/AIM: The anticancer potential of indomethacin and diclofenac has been reported against several types of cancer cells. In this study, we investigated the enhancement effect of a coumaric acid derivative found in some Piper plants, N-trans-p-coumaroyltyramine (TCT) on indomethacin and diclofenac cytotoxicity in breast cancer cells. MATERIALS AND METHODS: MCF-7 and mitoxantrone-resistant MCF-7 (MCF-7/MX) cancer cells were treated with indomethacin or diclofenac in the presence of TCT for 48 h. Cell viability, apoptosis, mitochondrial function and signaling proteins were assayed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Hoechst 33342, tetramethyl-rhodamine-ethyl-ester and western blot analysis, respectively. RESULTS: Combination treatment resulted in significant reduction of cell viability and mitochondrial membrane potential, whereas the ratio of BCL2-associated X, apoptosis regulator to BCL2 apoptosis regulator, and apoptosis increased. The enhancing effect of TCT was related to reduced nuclear factor-erythroid factor 2-related factor 2/heme oxygenase-1 expression, and increased activation of the protein kinase RNA-like endoplasmic reticulum kinase/eukaryotic initiation factor 2 alpha/activating transcription factor 4/C/EBP homologous protein signaling pathways. CONCLUSION: TCT in combination with indomethacin or diclofenac promoted endoplasmic reticulum stress-dependent apoptosis in breast cancer cells.

A new dihydrophenanthrene from Cymbidium finlaysonianum and structure revision of cymbinodin-A.

1-(4-Hydroxybenzyl)-4,6-dimethoxy-9,10-dihydrophenanthrene-2,7-diol (13), a new dihydrophenanthrene, was isolated along with ferulic acid esters (1), eight phenanthrene derivatives (2, 3, 6-11) and three bibenzyls (4, 5, 12) from an epiphytic orchid, Cymbidium finlaysonianum. The molecular structure of cymbinodin-A (2) was revised based on spectroscopic data and comparison with the literature. Compounds 2, 3, and 6-13 were evaluated and shown to be cytotoxic against human small cell lung cancer (NCI-H187) cell line. Cymbinodin-A displayed the highest cytotoxicity with an IC50 value of 3.73 µM.

Cytotoxic stilbenes from the roots of Paphiopedilum godefroyae.

Two new stilbenes, 2-(3',5'-dimethoxyphenyl)-6-hydroxy-5-methoxybenzofuran (1) and 3'-hydroxy-2,5'-dimethoxystilbene (2), together with seven known stilbenes (3, 5-10) and one flavanone (4), were isolated from the roots of Paphiopedilum godefroyae. Their chemical structures were determined on the basis of their spectroscopic data. These isolated compounds were evaluated for their cytotoxicity against human small cell lung cancer (NCI-H187) cell lines and an arylbenzofuran derivative, 5,6-dimethoxy-2-(3-hydroxy-5-methoxyphenyl)benzofuran (6), was shown to be strongly cytotoxic with an IC50 value of 5.10 µM.