Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G 1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. Mol Cancer Ther; 9(3); 718-30. ©2010 AACR.

Gold(III) complexes have shown promise as antitumor agents, but their clinical usefulness has been limited by their poor stability under physiological conditions. A novel gold(III) porphyrin complex [5-hydroxyphenyl-10,15,20-triphenylporphyrinato gold(III) chloride (gold-2a)] with improved aqueous stability showed 100-fold to 3,000-fold higher cytotoxicity than platinum-based cisplatin and IC 50 values in the nanomolar range in a panel of human breast cancer cell lines. Intraductal injections of gold-2a significantly suppressed mammary tumor growth in nude mice. These effects are attributed, in part, to attenuation of Wnt/β-catenin signaling through inhibition of class I histone deacetylase (HDAC) activity. These data, in combination with computer modeling, suggest that gold-2a may represent a promising class of anticancer HDAC inhibitor preferentially targeting tumor cells with aberrant Wnt/β-catenin signaling.

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The advent of a large-volume high-pressure apparatus has led to the discovery of many new materials with exceptional properties for widespread applications such as superhard materials (e.g., diamonds). However, for most conventional devices, the pressure and temperature capabilities are often limited to 6 GPa and 2300 K, which severely impedes the study of materials at extended pressures and temperatures. In this work, we present experimental optimizations of the high-pressure cell assembly for cubic press with a focus on the improvement of its temperature capability, leading to a record temperature value of ∼4050 K and largely extended pressure conditions up to ∼10 GPa with a centimeter-sized sample volume. Pressures of the new assembly at high temperatures are investigated by the melting-point method, giving rise to a series of parallel isoforce loading lines associated with thermally induced pressure. For the first time, the high-pressure melting curve of tungsten carbide is determined up to 3800 K and 8 GPa, and single-crystal refractory materials of Mo, Ta, and WC are also grown using the optimized cell.

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Using submicron cubic boron nitride (cBN) powder as a starting material, polycrystalline cBN (PcBN) samples without additives were sintered from 8.0–14.0 GPa at 1750 °C, and their sintering behaviour and mechanical properties were investigated. Transmission electron microscopy analysis showed that high-density nanotwins could be generated from common submicron cBN grains during high pressure and high temperature treatment. The dislocation glide and (111) mechanical micro-twinning are the main mechanisms that underlie plastic deformation in the sintering process, and this contributes to the grain refinement. A refinement in the grain size (∼120 nm), micro-defect (nanotwin and stacking faults), and strong covalent bonding between the grains are crucial for improving the sample mechanical properties. The PcBN sintered at 11.0 GPa/1750 °C possessed outstanding mechanical properties, including a high Vickers hardness (∼72 GPa), fracture toughness (∼12.4 MPam1/2), and thermal stability (∼1273 °C in air).