Yean-Jang Lee

Demethylwedelolactone derivatives inhibit invasive growth in vitro and lung metastasis of MDA-MB-231 breast cancer cells in nude mice.

The anticancer properties of demethylwedelolactone (DWEL) and wedelolactone (WEL), which are naturally occurring coumestans, have not been well characterized. In this study, we investigated the anti-invasive effects of synthetic WEL and DWEL on human MDA-MB-231 breast cancer cells. We found that WEL and DWEL inhibited the anchorage-independent growth and also suppressed cell motility and cell invasion of MDA-MB-231 cells. In addition, WEL and DWEL reduced the activity and expression of matrix metalloproteinases (MMPs) involved in blocking the IκB-α/NFκB and MEK/ERK signaling pathways in MDA-MB-231 cells. Furthermore, DWEL suppressed the metastasis and lung colonization of the tumor cells in the nude mice. Altogether, these data suggest that DWEL derivatives exert anti-invasive growth effect on breast cancer cells.

Antitumor progression potential of morusin suppressing STAT3 and NFκB in human hepatoma SK-Hep1 cells

Morusin is a prenylated flavonoid that has been isolated from the root bark of the mulberry tree (Morus species, Moraceae), a Chinese traditional medicine. It has been synthesized by our laboratory from commercially available phloroglucinol, and has demonstrated to possess antitumor effects of cell lines including A549, MCF-7, and MDA-MB-231. In this study, at non-cytotoxic concentrations, morusin altered invasive morphology and suppressed cell-matrix adhesion, cell motility and cell invasion in SK-Hep1 cells. Morusin also increased the expression of E-cadherin, an epithelial cell junction protein, decreased the expression of vimentin, a mesecnchymal marker, and α2-, α6-, β1- integrin, which regulated cancer attachment and migration. In addition, morusin reduced the activity of matrix metalloproteinase-2 and 9 (MMP-2 and MMP-9), which were involved in extracellular matrix (ECM) degradation and promoting cancer cell invasion. Furthermore, morusin suppressed the signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NFκB) signaling pathways, which modulate the protein expression involved in the invasion process. Finally, morusin decreased the lung colonization of the SK-Hep1 cells in the nude mice. These results indicate morusin possesses antitumor progression potential through suppressing STAT3 and NFκB.

Inhibition of cell survival, cell cycle progression, tumor growth and cyclooxygenase-2 activity in MDA-MB-231 breast cancer cells by camphorataimide B

Both mycelium and fruiting body of Antrodia camphorate, a traditional medicinal fungus of the family Polyporaceae in Taiwan, have been suggested to possess multiple biological functions. However, there is little information on the anticancer components and actions of mycelium of Antrodia camphorate. In the present study, the anticancer potential of synthesized maleimide derivatives, which have been isolated from mycelium of Antrodia camphorate, is examined. Comparing the cytotoxicity of two synthesized maleimide derivatives in four human cancer cell lines, camphorataimide B displayed potent efficacy. Then we investigated the impact of camphorataimide B on cell survival and cell cycle progression in vitro, and tumor growth in vivo in MDA-MB-231 breast cancer cells. Camphorataimide B decreased the cell viability and foci formation of MDA-MB-231 breast cancer cells. Further, camphorataimide B triggered apoptosis and blocked cell cycle progression of MDA-MB-231 breast cancer cells. Using immunoblotting analysis, camphorataimide B decrease the expression of cyclin-A and cyclin-B1. Moreover, we demonstrated for the first time that camphorataimide B inhibited cyclooxygenase-2 (COX-2) activity and protein expression in MDA-MB-231 cells. In nude mice study, camphorataimide B administration retarded the xenograft tumor growth of MDA-MB-231 cells. By immunohistochemical analysis, camphorataimide B decreased the expression of Ki-67 in xenograft tumor in vivo. It implied that camphorataimide B blocked cell cycle progression. Consistent with the cell culture investigation, camphorataimide B also reduced the expression of cyclin-A, cyclin-B1 and COX-2 in xenograft tumor. Thus, camphorataimide B may play a crucial role in prevention and therapy of malignant breast cancer.

Total Synthesis of (±)-Armepavines and (±)-Nuciferines From (2-Nitroethenyl)benzene Derivatives

A concise route to armepavine 1 and nuciferine 2 and 3, which can be isolated from the leaves of Nelumbo nucifera (Nymphaceae), has been achieved in which the longest linear sequence is only six steps from commercially available benzaldehyde in 28%, 21%, and 20% overall yield, respectively. The key transformations in the synthesis are the radical cyclization of aryl bromide with Bu3SnH and the Pictet–Spengler reaction of N-substituted amine with aldehyde.

Calanquinone A induces anti-glioblastoma activity through glutathione-involved DNA damage and AMPK activation.

Glioblastoma, a highly malignant glioma, is resistant to both radiation and chemotherapy and is an intractable problem in clinical treatment. New therapeutic approaches are in urgent need. Calanquinone A, an herbal constituent, displayed anti-proliferative activity against glioblastoma cells, including A172, T98 and U87. Flow cytometric analysis showed an S phase arrest and a subsequent apoptosis to calanquinone A action. Further identification demonstrated a rapid increase of γH2A.X formation at S phase. The data together with comet tail formation and Chk1 activation indicated DNA damage response. N-acetyl cysteine (an antioxidant and a glutathione precursor) and exogenously applied glutathione, but not trolox (an antioxidant), completely abolished calanquinone A-induced effects. Immunofluorescence assay revealed that calanquinone A decreased the intracellular glutathione levels in both A172 and T98 cells. However, calanquinone A, by itself, did not conjugate glutathione. The data suggested that the decrease of cellular glutathione predominantly contributed to the anticancer mechanism. Furthermore, calanquinone A induced the activation of AMP-activated protein kinase (AMPK) and the inhibition of p70S6K activity. Rhodamine efflux assay showed that calanquinone A did not block efflux activity, indicating that calanquinone A was not a P-glycoprotein substrate. In summary, the data suggest that calanquinone A displays anti-glioblastoma activity through a decrease of cellular glutathione levels that subsequently induces DNA damage stress and AMPK activation, leading to cell cycle arrest at S-phase and apoptotic cell death. Furthermore, calanquinone A does not serve as a P-glycoprotein substrate, suggesting a potential for further development in anti-glioblastoma therapy.

Total Synthesis of Moscatilines and Wedelolactones as Potential Inhibitors of Anti-Metastic Agents in MDA-MB-231 Cells

Combretastatins, which are an important group of anticancer drugs, were isolated by Pettit et al. from the African tree Combretum caffrum in 1989. Additionally, Liang et al. have reported that ten coumestans were isolated from the roots of Hedysarum multijugum, which is a plant in Hedysarum Linn. of the family Leguminosae used as a folk herbal drug in northwest China. Coumestans comprise a class of naturally occurring products with a variety of biological activities including phytoestrogenic, antibacterial, antifungal, antimyotoxic, and phytoalexine effects. Due to their biological activities, the synthesis of Hedysarimcoumestan B is achieved in which the longest linear sequence is only eight steps in 50% overall yield from commercially available phloroglucinol. The key transformations in the synthesis are Stille coupling and DDQ oxidative-cyclization reactions. This synthetic strategy can be applied to give access to the demethylwedelolactone and wedelolactone, which were afforded from α-bromocoumarin in high 55% and 47% yields, respectively. In addition, CA-4 analogues are also synthesized by Pd-catalyzed coupling in overall yield 20∼28%. Furthmore, the molecular model was examined the interactions of proteins and ligands as well. Finally, the bioassay results show that the anti-invasion and anti-metastsis activity of wedelolactones in breast cancer are associated with inhibition of signaling pathway and promotion of chromatin remodeling. Camphorataimide B reduced the size and weigth of lung as well as lung colonization of MDA-MB-231 cells.