A New Perspective for Osteosarcoma Therapy: Proteasome Inhibition by MLN9708/2238 Successfully Induces Apoptosis and Cell Cycle Arrest and Attenuates the Invasion Ability of Osteosarcoma Cells in Vitro.

BACKGROUND: The proteasome exists in all eukaryotic cells and provides the main route of intracellular proteins degradation involved in cell growth and apoptosis. Proteasome inhibition could block protein degradation pathways and disturb regulatory networks, possibly leading to profound effects on cell growth, particularly in cancer cells. A proteasome inhibitor with an appropriate toxicity index for malignant cells rather than normal cells would be an attractive anticancer therapy. METHODS: The human osteosarcoma (OS) cell lines MG-63 and Saos-2 and normal osteoblast cells were used to study the antitumour activity of the proteasome inhibitor MLN9708/2238. RESULTS: MLN2238 inhibited cell growth, induced cell cycle arrest and apoptosis, and attenuated the invasion abilities of MG-63 and Saos-2 cells, with little cytotoxicity to normal cells. In addition, MLN2238 promoted antitumour mechanisms including the accumulation of E2F1, P53, P21 and other negative G2/M checkpoint proteins; up-regulated the relative expression ratio of BAX/BCL-2, APAF-1 and pro-apoptotic proteins of the BCL-2 family; triggered mitochondrial outer membrane permeabilization (MOMP); down-regulated BCL-2 and XIAP; activated caspase3/8/9; and suppressed MMP2/9 expression and secretion levels. CONCLUSIONS: The proteasome may be a novel biochemical target for OS treatment in vitro. Our study provides a promising mechanistic framework for MLN9708/2238 in OS treatment, supporting its clinical development.

Relationship between biomass, seed components and seed Cd concentration in various peanut (Arachis hypogaea L.) cultivars grown on Cd-contaminated soils.

Peanuts (Arachis hypogaea L.) exhibit high genotypic variations in seed Cd accumulation, but the mechanism remains unclear. This study aimed to reveal the main factors that determine Cd concentration in peanut seeds. The biomasses and Cd accumulation in plant tissues as well as the Cd distribution in the seeds of 15 peanut cultivars were analyzed in a pot experiment at 4mgkg(-1) Cd (treatment) and 0mgkg(-1) Cd (control). Peanuts exhibited large variations among cultivars in terms of Cd accumulation and distribution at the whole-plant and seed levels. The peanut cultivars were divided into three groups based on [Cd]embryos as follows: (i) high Cd accumulators (Zhenghong 3 and Haihua 1), (ii) low Cd accumulators (Qishan 208, Luhua 8, and Yuhua 15), and (iii) intermediate Cd accumulators (10 remaining cultivars). [Cd]embryos was significantly correlated with [Cd]testae and [Cd]oils at control conditions, whereas in the 4mgkg(-1) Cd treatment, [Cd]embryos was negatively correlated with plant biomass, total Cd and its proportion in vegetative organs, and seed oil contents. [Cd]embryos was positively correlated with protein contents, [Cd]oils, and proportion of Cd in protein extracts at 4mgkg(-1) Cd treatments. The attenuation of Cd by high biomass of vegetative tissues and Cd-binding proteins in seeds mainly determined the Cd concentration in peanut seeds.

Effects of drought on cadmium accumulation in peanuts grown in a contaminated calcareous soil.

This study aimed to investigate the effects of drought stress on cadmium (Cd) accumulation in peanut (Arachis hypogaea L.) grown in contaminated calcareous soils. Five peanut cultivars were grown in a calcareous soil spiked with 4 mg Cd kg(-1) soil (dry weight) under well-watered, mild drought, and severe drought conditions. The biomass production, gas exchange, spectral reflectance, and Cd accumulation in plant tissues were determined. The five cultivars significantly differed from each other in biomass production, gas exchange, spectral reflectance, and Cd accumulation. The effect of drought on Cd accumulation in peanuts varies with plant tissues, cultivars, and developmental stages. Drought decreased root Cd concentrations in seedlings of the two high Cd-accumulating cultivars (Haihua 1 and Zhenghong 3), which is associated with increasing leaf active Fe content. However, for the mature plants, drought stress caused an increase in Cd accumulation in roots, pod walls, and seeds depending on peanut cultivars. Negative correlations were found between seed Cd concentration and biomasses in both preflowering seedlings and mature plants. The seed Cd concentration in mature plants was also observed to be positively correlated with the shoot Cd concentration in preflowering seedlings. The increased Cd concentration in seeds of drought-stressed peanut plants grown in Cd-contaminated calcareous soils might be attributed to the drought-induced decrease of biomass production.