CD14(+)S100A9(+) inflammatory monocytes in patients with NSCLC are a distinct subset of MDSCs, which suppress T cells by arginase, iNOS, and the IL-13/IL-4Rα axis. The amount of these inflammatory monocytes is associated with poor response to chemotherapy. Clinical trial registered with www.clinicaltrials.gov (NCT 01204307).

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Drug resistance is one of the main obstacles to the successful treatment of cancer. The availability of agents that are highly effective against drug-resistant cancer cells is therefore essential. The present study was performed to examine the anticancer effects of evodiamine, a major constituent of the Chinese herb Evodiae fructus, in adriamycin-resistant human breast cancer NCI/ADR-RES cells. Evodiamine inhibited the proliferation of NCI/ADR-RES cells in a concentration-dependent manner with a GI50 of 0.59 +/- 0.11 microM. This agent also caused a substantial apoptosis at 1 microM. FACScan flow cytometric analysis of cell cycle progression revealed that a G2/M arrest was initiated after a 12-h exposure to the drug. Evodiamine increased tubulin polymerization as determined by the immunocytochemical and in vivo tubulin polymerization analyses. In a time- and concentration-dependent manner, evodiamine also promoted the phosphorylations of Raf-1 kinase and Bcl-2. The phosphorylation site of Raf-1 kinase was identified to be serine338. The in vivo anticancer effects of evodiamine were evaluated in Balb-c/nude mice following a tumor xenograft implantation of NCI/ADR-RES cells. The antitumor activity of evodiamine against the human multiple-drug resistant tumor xenograft was found to be superior to that of paclitaxel. Evodiamine therefore represents a highly promising chemotherapeutic agent in the treatment of human multiple-drug resistant cancer cells.

Nineteen compounds have been isolated from the methanol extract of the root and aerial parts of Ruta graveolens. The structural elucidation of these isolated compounds were determined by the spectroscopic methods and/or comparison of the physical data with literature values. Their antiplatelet aggregation and cytotoxic activities were examined to find potent antiplatelet aggregation and cytotoxic compounds from natural resources. Among them, dictamine (5), skimmianine (7), psoralen (8), chalepensin (12), clausindin (13), and graveolinine (16) showed significant inhibition of platelet aggregation, induced by arachidonic acid and collagen. Arborinine (2), dictamine (5), isopimpinellin (11), clausindin (13), and graveoline (17) exhibited cytotoxic activity against KB, Hela, DLD, NCI and Hepa tumor cell lines.

A new aporphine, N-(N-methylcarbamoyl)-O-methyl-bulbocapnine (1), together with seven known compounds, (-)-5'-methoxypodorhizol (2), a mixture of beta-sitosterone (3) and stigmasta-4,22-dien-3-one (4), a mixture of 3 beta-hydroxystigmast-5-en-7-one (5) and 3 beta-hydroxystigmasta-5,22-dien-7-one (6), and a mixture of 6 alpha-hydroxystigmast-4-en-3-one (7) and 6 alpha-hydroxystigmasta-4,22-dien-3-one (8), were isolated in continuing studies on the trunk bark of Formosan Hernandia nymphaeifolia. The structures of these compounds were determined through spectral analyses. In addition, the previously reported six alkaloids, laurotetanine, oxohernagine, thalicarpine, reticuline, (+)-vateamine-2'-beta-N-oxide, (+)-hernandaline and six lignans, (+)-epiaschantin, (+)-epimagnolin, (+)-epiyangambin, (-)-hernone, (-)-yatein, (-)-deoxypodophyllotoxin were demonstrated to have anti-platelet aggregation activity.

Heteronemin is a bioactive marine sesterterpene isolated from the sponge Hyrtios sp. Previous reports have shown that heteronemin possesses anticancer activity. Here, heteronemin displayed cytotoxic effects against three human cancer cell lines (A549, ACHN, and A498) and exhibited potent activity in A498 human renal carcinoma cells, with an IC50 value of 1.57 μM by MTT assay and a GI50 value of 0.77 μM by SRB assay. Heteronemin initiates apoptotic cell death by downregulating Bcl-2 and Bcl-xL and upregulating Bax, leading to the disruption of the mitochondrial membrane potential and the release of cytochrome c from the mitochondria. These effects were associated with the activation of caspase-3/caspase-8/caspase-9, followed by PARP cleavage. Furthermore, heteronemin inhibited the phosphorylation of AKT signaling pathway and ERK and activated p38 and JNK. The specific inhibition of the p38 pathway by SB203580 or p38 siRNA treatment reversed the heteronemin-induced cytotoxicity and apoptotic signaling. Heteronemin also induced autophagy in A498 cells, and treatment with chloroquine (autophagy inhibitor) or SP600125 (JNK inhibitor) inhibited autophagy and increased heteronemin-induced cytotoxicity and apoptotic signaling. Taken together, this study proposes a novel treatment paradigm in which the combination of heteronemin and autophagy inhibitors leads to enhanced RCC cell apoptosis.

BackgroundThe aim of this study was to determine the molecular mechanisms of physalin F, an effective purified extract of Physalis angulata L. (Solanacae), in renal carcinoma A498 cells.Methodology/Principal FindingsPhysalin F was observed to significantly induce cytotoxicity of three human renal carcinoma A498, ACHN, and UO-31 cells in a concentration-dependent manner; this was especially potent in A498 cells. The physalin F-induced cell apoptosis of A498 cells was characterized by MTT assay, nuclear DNA fragmentation and chromatin condensation. Using flow cytometry analysis, physalin F induced A498 cell apoptosis as demonstrated by the accumulation of the sub-G1 phase in a concentration- and time-dependent manner. Moreover, physalin F-mediated accumulation of reactive oxygen species (ROS) caused Bcl-2 family proteins, Bcl-2, and Bcl-xL degradation, which led to disruption of mitochondrial membrane potential and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-3 and caspase-9 activity, which led to poly(ADP-ribose) polymerase cleavage. However, the antioxidant N-acetyl-L-cysteine (NAC) and glutathione (GSH) resulted in the inhibition of these events and reversed physalin F-induced cell apoptosis. In addition, physalin F suppressed NF-κB activity and nuclear translocation of p65 and p50, which was reversed by NAC and GSH.ConclusionPhysalin F induced cell apoptosis through the ROS-mediated mitochondrial pathway and suppressed NF-κB activation in human renal cancer A498 cells. Thus, physalin F appears to be a promising anti-cancer agent worthy of further clinical development.

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