salubrinal and pyrazolanthrone

Tubeimoside-1 (TBMS1), a triterpenoid saponin extracted from the Chinese herbal medicine Bolbostemma paniculatum (Maxim) Franquet (Cucurbitaceae), has shown anticancer activities in various cancer cell lines. The aim of this study was to investigate the anticancer activity and molecular targets of TBMS1 in human prostate cancer cells in vitro.. DU145 and P3 human prostate cancer cells were treated with TBMS1. Cell viability and apoptosis were detected. ROS generation, mitochondrial membrane potential and cell cycle profile were examined. Western blotting was used to measure the expression of relevant proteins in the cells.. TBMS1 (5-100 μmol/L) significantly suppressed the viability of DU145 and P3 cells with IC50 values of approximately 10 and 20 μmol/L, respectively. Furthermore, TBMS1 dose-dependently induced apoptosis and cell cycle arrest at G0/G1 phase in DU145 and P3 cells. In DU145 cells, TBMS1 induced mitochondrial apoptosis, evidenced by ROS generation, mitochondrial dysfunction, endoplasmic reticulum stress, modulated Bcl-2 family protein and cleaved caspase-3, and activated ASK-1 and its downstream targets p38 and JNK. The G0/G1 phase arrest was linked to increased expression of p53 and p21 and decreased expression of cyclin E and cdk2. Co-treatment with Z-VAD-FMK (pan-caspase inhibitor) could attenuate TBMS1-induced apoptosis but did not prevent G0/G1 arrest. Moreover, co-treatment with NAC (ROS scavenger), SB203580 (p38 inhibitor), SP600125 (JNK inhibitor) or salubrinal (ER stress inhibitor) significantly attenuated TBMS1-induced apoptosis.. TBMS1 induces oxidative stress-mediated apoptosis in DU145 human prostate cancer cells in vitro via the mitochondrial pathway.

Topics: Acetylcysteine; Amino Acid Chloromethyl Ketones; Anthracenes; Apoptosis; Caspase 3; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Cinnamates; Cyclin E; Cyclin-Dependent Kinase 2; Dose-Response Relationship, Drug; Endoplasmic Reticulum Stress; G1 Phase; Humans; Imidazoles; JNK Mitogen-Activated Protein Kinases; Male; MAP Kinase Kinase Kinase 5; Membrane Potential, Mitochondrial; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Prostatic Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyridines; Reactive Oxygen Species; Resting Phase, Cell Cycle; Saponins; Thiourea; Triterpenes

Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-

Topics: Animals; Anthozoa; Anthracenes; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Cell Survival; Cinnamates; Diterpenes; Endoplasmic Reticulum Stress; Gene Expression Regulation, Neoplastic; Humans; JNK Mitogen-Activated Protein Kinases; Liver Neoplasms; Mitochondria; Signal Transduction; Thiourea; Transcription Factor CHOP; Unfolded Protein Response

Endoplasmic reticulum stress (ERS) can initiate inflammation, and the coupling of these responses is thought to be fundamental to the pathogenesis of cardiovascular disease. However, the mechanism linking ERS and inflammation in myocardial ischemia/reperfusion needs further investigation. Cultured cardiomyocytes were pretreated with SP600125 or salubrinal, followed by tunicamycin to clarify the involvement of the IRE1α and PERK pathways in ERS inflammation. The cardiomyocytes were given hypoxia/reoxygenation (H/R), and the effects of the NF-κB inhibitor, SN50, were followed. GRP78 protein levels were similar in the tunicamycin (Tm), salubrinal, and SP600125 groups, but were lower in cells treated with SN50. SN50 might effectively block the H/R-induced link between ERS and inflammation in cardiomyocytes by decreasing GRP78. This knowledge will aid in the development of therapies for myocardial ischemia/reperfusion injury.

Topics: Animals; Anthracenes; Cell Hypoxia; Cells, Cultured; Cinnamates; eIF-2 Kinase; Endoplasmic Reticulum Stress; Endoribonucleases; Heart Rate; Heat-Shock Proteins; Inflammation; Multienzyme Complexes; Myocytes, Cardiac; NF-kappa B; Peptides; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Thiourea; Tumor Necrosis Factor-alpha; Tunicamycin

Statins are effective cholesterol-lowering drugs that exert pleiotropic effects, including cytotoxicity to cancer cells. We previously reported that simvastatin triggered the mitochondrial apoptotic pathway in MethA fibrosarcoma cells, which was accompanied by the translocation of stabilized p53 to the mitochondria. In this study, we investigated whether statins induce the endoplasmic reticulum (ER) stress response and the mechanisms by which this response is linked to the stabilization of p53 and its translocation to the mitochondria. Statins induced typical ER stress-related proteins, such as BiP/78 kDa glucose-regulated protein (Grp78) and CCAAT/enhancer-binding protein homologous protein (CHOP), as well as the phosphorylation of protein kinase RNA-like endoplasmic reticulum kinase (PERK), eIF2α and JNK. The statin-induced phosphorylation of eIF2α and JNK was inhibited by supplementation with components of the mevalonate pathway, such as mevalonate, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP). Salubrinal, an inhibitor of the dephosphorylation of eIF2α, suppressed the loss of mitochondrial membrane potential and the translocation of stabilized p53 and Bax to the mitochondria; however, SP600125, a JNK kinase inhibitor, did not exert this effect. Furthermore, the eIF2α knockdown sensitized cells to simvastatin-induced apoptosis and the overexpression of a non-phosphorylatable eIF2α-mutant [serine 51(Ser51)/alanine] enhanced the stabilization of p53 and its translocation to the mitochondria in response to simvastatin treatment. Taken together, these data indicate that eIF2α phosphorylation in the context of the ER stress response plays a role in cell survival by counteracting the p53-mediated mitochondrial apoptosis in response to statins.

Topics: Animals; Anthracenes; Anticholesteremic Agents; Apoptosis; bcl-2-Associated X Protein; Cell Line, Tumor; Cell Survival; Cinnamates; eIF-2 Kinase; Endoplasmic Reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Eukaryotic Initiation Factor-2; Fibrosarcoma; Heat-Shock Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; JNK Mitogen-Activated Protein Kinases; Membrane Potential, Mitochondrial; Mevalonic Acid; Mice; Mitochondria; Phosphorylation; Polyisoprenyl Phosphates; Protein Transport; RNA Interference; RNA, Small Interfering; Sesquiterpenes; Signal Transduction; Simvastatin; Thiourea; Transcription Factor CHOP; Tumor Suppressor Protein p53

CD70 is expressed in normal activated immune cells as well as in several types of tumors. It has been established that anti-CD70 mAb induces complement-dependent death of CD70(+) tumor cells, but how anti-CD70 mAb affects the intrinsic signaling is poorly defined. In this report, we show that ligation of CD70 expressed on EBV-transformed B cells using anti-CD70 mAb induced production of reactive oxygen species (ROS) and subsequent apoptosis. We observed an early expression of endoplasmic reticulum (ER) stress response genes that preceded the release of apoptotic molecules from the mitochondria and the cleavage of caspases. CD70-induced apoptosis was inhibited by pretreatment with the ER stress inhibitor salubrinal, ROS quencher N-acetylcysteine, and Ca(2+) chelator BAPTA. We supposed that ROS generation might be the first event of CD70-induced apoptosis because N-acetylcysteine blocked increases of ROS and Ca(2+), but BAPTA did not block ROS generation. We also found that CD70 stimulation activated JNK and p38 MAPK. JNK inhibitor SP600125 and p38 inhibitor SB203580 effectively blocked upregulation of ER stress-related genes and cleavage of caspases. Inhibition of ROS generation completely blocked phosphorylation of JNK and p38 MAPK and induction of ER stress-related genes. Taken together, we concluded that cross-linking of CD70 on EBV-transformed B cells triggered ER stress-mediated apoptosis via ROS generation and JNK and p38 MAPK pathway activation. Our report reveals alternate mechanisms of direct apoptosis through CD70 signaling and provides data supporting CD70 as a viable target for an Ab-based therapy against EBV-related tumors.

Topics: Acetylcysteine; Animals; Anthracenes; Antibodies, Monoclonal; Apoptosis; B-Lymphocytes; Callithrix; CD27 Ligand; Cell Line, Transformed; Chelating Agents; Cinnamates; Egtazic Acid; Endoplasmic Reticulum; Epstein-Barr Virus Infections; Free Radical Scavengers; Herpesvirus 4, Human; MAP Kinase Kinase 4; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Thiourea; Unfolded Protein Response