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Aberrant reactions of signal transducer and transcriptional activator (STAT) are frequently detected in multiple myeloma (MM) cancers and can upregulate the expression of multiple genes related to cell proliferation, survival, metastasis, and angiogenesis. Therefore, agents capable of inhibiting STAT activation can form the basis of novel therapies for MM patients. In the present study, we investigated whether the potential anti-cancer effects of Formononetin (FT), a naturally occurring isoflavone derived from Astragalus membranaceus, Trifolium pratense, Glycyrrhiza glabra, and Pueraria lobata, against MM cell lines and human multiple myeloma xenograft tumors in athymic nu/nu mice model are mediated through the negative regulation of STAT3 and STAT5 pathways. Data from the in vitro studies indicated that FT could significantly inhibit cell viability, and induce apoptosis. Interestingly, FT also suppressed constitutive STAT3 (tyrosine residue 705 and serine residue 727) and STAT5 (tyrosine residue 694/699) activation, which correlated with the suppression of the upstream kinases (JAK1, JAK2, and c-Src) in MM cells, and this effect was found to be mediated via an increased production of reactive oxygen species (ROS) due to GSH/GSSG imbalance. Also, FT abrogated STAT3 and STAT5 DNA binding capacity and nuclear translocation. FT induced cell cycle arrest, downregulated the expression of STAT3-regulated anti-apoptotic, angiogenetic, and proliferative gene products; and this correlated with induction of caspase-3 activation and cleavage of PARP. Intraperitoneal administration of FT significantly suppressed the tumor growth in the multiple myeloma xenograft mouse model without exhibiting any significant adverse effects. Overall, our findings indicate that FT exhibits significant anti-cancer effects in MM that may be primarily mediated through the ROS-regulated inhibition of the STAT3 and STAT5 signaling cascade. [ABSTRACT FROM AUTHOR]

Background: Ophiopogonin D (OP-D), a steroidal glycoside obtained from the Chinese medicinal plant Ophiopogonin japonicas (the root portion), has been traditionally used to treat fever, inflammation, cough, sputum etc. However, the detailed molecular mechanism(s) underlying its therapeutic actions is still unknown.Hypothesis: Because nuclear factor-κB (NF-κB), PI3K/AKT, and activator protein-1 (AP-1) signaling cascades have significant functions in cell proliferation, inflammation, and angiogenesis in tumor cells, we hypothesized that OP-D may disrupt these signaling cascades to exert its anticancer effects in human lung-cancer cells.Methods: We evaluated the effect of OP-D on multiple signaling cascades and its regulated functional responses in lung cancer cells.Results: OP-D blocked both basal and cytokine-induced proliferation of human lung-cancer cells and caused down-regulation of the expression of diverse oncogenic gene products through the suppression of NF-κB, PI3K/AKT, and AP-1 pathways; but did not affect JNK, p38 and ERK MAP kinases. Interestingly, OP-D suppressed constitutive NF-κB activation in lung cancer cells via interfering with the IκB kinase activation, which inhibited phosphorylation and caused degradation of IκB-α. OP-D also blocked phosphorylation and the nuclear translocation of p65, thereby suppressing NF-κB reporter activity in lung cancer cells. Besides, OP-D could augment cell death induced by paclitaxel in lung-cancer cells.Conclusion: Overall, the data indicates that OP-D may abrogate diverse signaling cascades linked to tumorigenesis, and can be used in combination with chemotherapeutic agents for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Signal transducer and activator of transcription 3 (STAT3) is persistently activated in squamous cell carcinoma of the head and neck (SCCHN) and can cause uncontrolled cellular proliferation and division. Hypothesis: Thus, its targeted abrogation could be an effective strategy to reduce the risk of SCCHN. Resveratrol is known for its anti-cancer efficacy in a variety of cancer models. Study Design: The effect resveratrol on STAT3 activation, associated protein kinases, phosphatases, cellular proliferation and apoptosis was investigated. Methods: We evaluated the effect of resveratrol on STAT3 signaling cascade and its regulated functional responses in SCCHN cells. Results: We found that HN3 and FaDu cells expressed strongly phosphorylated STAT3 on both tyrosine 705 and serine 727 residues as compared to other SCCHN cells. The phosphorylation was completely suppressed by resveratrol in FaDu cells, but not substantially in HN3 cells. STAT3 suppression was mediated through the inhibition of activation of upstream JAK2, but not of JAK1 and Src kinases. Treatment with the protein tyrosine phosphatase (PTP) inhibitor pervanadate reversed the resveratrol-induced down-regulation of STAT3, thereby indicating a critical role for a PTP. We also found that resveratrol induced the expression of the SOCS-1 protein and mRNA. Further, deletion of SOCS-1 gene by siRNA suppressed the induction of SOCS-1, and reversed the inhibition of STAT3 activation. Resveratrol down-regulated various STAT3-regulated gene products, inhibited proliferation, invasion, as well as induced the cell accumulation in the sub-G1 phase and caused apoptosis. Beside, this phytoalexin also exhibited the enhancement of apoptosis when combined with ionizing radiation treatment. Conclusion: Our results suggest that resveratrol blocks STAT3 signaling pathway through induction of SOCS-1, thus attenuating STAT3 phosphorylation and proliferation in SCCHN cells. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To know the effect of adenosine 5′-triphosphate (ATP) on intracellular calcium level and cell proliferation in cervical cancer cells. Study design: Four different human cervical cancer cell lines (Caski, C33A, HeLaS3 and SiHa) were used in this study. The change of intracellular calcium level, cell proliferation and the activity of proliferation- and calcium-related transcription factors by extracellular ATP were examined in these cell lines. Results: Extracellular ATP induced calcium mobilization, cell proliferation and the activation of NF-κB in all cell lines used. Conclusion: These results suggest that calcium mobilization and NF-κB dependent signaling pathway play an important role in the cell proliferation by ATP in cervical cancer. [Copyright &y& Elsevier]

Abstract: Since its initial identification and cloning in 2002, Astrocyte Elevated Gene-1 (AEG-1), also known as metadherin (MTDH), 3D3 and LYsine-RIch CEACAM1 co-isolated (LYRIC), has emerged as an important oncogene that is overexpressed in all cancers analyzed so far. Examination of a large cohort of patient samples representing diverse cancer indications has revealed progressive increase in AEG-1 expression with stages and grades of the disease and an inverse relationship between AEG-1 expression level and patient prognosis. AEG-1 functions as a bona fide oncogene by promoting transformation. In addition, it plays a significant role in invasion, metastasis, angiogenesis and chemoresistance, all important hallmarks of an aggressive cancer. AEG-1 is also implicated in diverse physiological and pathological processes, such as development, inflammation, neurodegeneration, migraine and Huntington''s disease. AEG-1 is a highly basic protein with a transmembrane domain and multiple nuclear localization signals and it is present in the cell membrane, cytoplasm, nucleus, nucleolus and endoplasmic reticulum. In each location, AEG-1 interacts with specific proteins thereby modulating diverse intracellular processes the combination of which contributes to its pleiotrophic properties. The present review provides a snapshot of the current literature along with future perspectives on this unique molecule. [Copyright &y& Elsevier]

Ethnopharmacological relevance Anti-inflammatory effects of Angelica dahurica (AD) have been reported in previous studies. In this study, we investigated the anti-inflammatory effects of AD on periodontitis. Materials and methods Male Sprague-Dawley rats aged 7 weeks (n=7) were subjected to ligature around bilateral mandibular first molars. 1 and 100 mg/mL of AD were topically applied to first molars for 14 days. Histological changes were observed in gingival epithelial layer, and the thickness of the gingival epithelial layer as well as the number of epithelial cells were quantified. To investigate the mRNA expression of pro-inflammatory cytokines in gingival tissues, reverse transcriptase polymerase chain reaction was performed. To confirm the anti-inflammatory effects of AD, pro-inflammatory mediators including cytokines and NF-kB, COX-2, and iNOS were analyzed in LPS-stimulated Raw 264.7 cells. Results Topical application of AD attenuated not only the thickness of epithelial layer, also the number of epithelial cells in gingival tissue. The expressions of IL-1β, IL-6, IL-8, and IFN-γ in gingiva were significantly reduced by AD treatment. Additionally, the expressions of IL-1β, IL-6, IL-8 and IFN-γ mRNA were inhibited by AD in LPS-treated RAW264.7 macrophage cells. Furthermore, AD treatment decreased LPS-induced elevation of NF-κB, COX-2 and iNOS protein levels in RAW264.7 cells. Conclusion Taken together, AD application ameliorated the hyperplasia of gingival epithelial layer by down-regulating pro-inflammatory mediators. AD might have therapeutic potentials for periodontal diseases. [ABSTRACT FROM AUTHOR]

Cynanchum atratum Bunge (Apocynaceae) is a folk medicine to treat skin inflammatory diseases. However, the effects of C. atratum on atopic dermatitis have not been elucidated. In this study, we evaluate the effects of aqueous extract of C. atratum (CA) and its molecular mechanism on atopic dermatitis (AD). 1 and 100 mg/mL CA were topically applied to 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin lesions for 11 days. The number of scratching behavior was evaluated for 20 min. AD-like symptoms including elevated serum IgE, skin hyperplasia and mast cell infiltration were investigated. The expressions of pro-inflammatory cytokines and mediators were analyzed in AD-like skin legions. In addition, pro-inflammatory cytokine production was confirmed in human mast cells (HMC)-1 stimulated with PMA plus A23187 (PMACI). Topical application of CA attenuated total serum IgE level and scratching behavior. Skin hyperplasia including epidermis and dermis was ameliorated in CA-treated skin legions. The number of infiltrated mast cells was significantly decreased by CA treatment. In addition, CA reduced pro-inflammatory cytokines, such as IL-6, IL-1β and TNF-α and Th2 cytokine, IL-4, in both of AD-like skin lesions and PMACI-sensitized HMC-1 cells. Furthermore, CA decreased the expressions of NF-κB, phospho-IκBα and MAP kinase. These results suggest the inhibitory effects of CA on the development of AD by regulating pro-inflammatory cytokines and mediators. CA could be an effective substance for the treatment of AD. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a metabolic syndrome that results from target-tissue resistance to insulin. Obesity is the condition of excess body fat accumulation. T2DM and obesity are both associated with hypertension, hyperlipidemia, and abdominal obesity. In Korean medicine, Yangkyuksanhwa-tang (YKSHT) has been prescribed for patients with T2DM. Oral glucose tolerance tests (OGTT), multiplex assays and hemoglobin A 1C (HbA1C) assessments were performed to determine the anti-diabetic effects of YKSHT and two major compositions of YKSHT, Lonicera japonica Thunb. (LJT) and Rehmannia glutinosa (RG) on db/db mice, a rodent model for T2DM. To study the anti-obesitic effects of LJT, RG or YKSHT, blood profiling including the triglycerides (TGs) and the total, LDL and HDL cholesterol levels were measured. In addition, body index measures such as the liver, retroperitoneal and epididymal fat tissues were collected and weighed. Mice treated with RG or YKSHT showed reduced blood glucose levels after stimulating the plasma GLP-1 levels. The multiplex assay results support the weight-controlling effects of the LJT, RG and YKSHT treatments, showing reducing levels of ghrelin and the induction of peptide YY (PYY) secretion. The YKSHT treatment reduced plasma TG levels and increased HDL cholesterol levels. The weights of the liver, retroperitoneal and epididymal fat tissues were reduced after the YKSHT treatment. Hence, we suggest that YKSHT can be utilized for the prevention and treatment of T2DM and obesity simultaneously. [ABSTRACT FROM AUTHOR]

Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD. [ABSTRACT FROM AUTHOR]

Abstract: Both PI3K/AKT/mTOR/S6K1 and mitogen activated protein kinase (MAPK) signaling cascades play an important role in cell proliferation, survival, angiogenesis, and metastasis of tumor cells. In the present report, we investigated the effects of β-caryophyllene oxide (CPO), a sesquiterpene isolated from essential oils of medicinal plants such as guava (Psidium guajava), oregano (Origanum vulgare L.), cinnamon (Cinnamomum spp.) clove (Eugenia caryophyllata), and black pepper (Piper nigrum L.) on the PI3K/AKT/mTOR/S6K1 and MAPK activation pathways in human prostate and breast cancer cells. We found that CPO not only inhibited the constitutive activation of PI3K/AKT/mTOR/S6K1 signaling cascade; but also caused the activation of ERK, JNK, and p38 MAPK in tumor cells. CPO induced increased reactive oxygen species (ROS) generation from mitochondria, which is associated with the induction of apoptosis as characterized by positive Annexin V binding and TUNEL staining, loss of mitochondrial membrane potential, release of cytochrome c, activation of caspase-3, and cleavage of PARP. Inhibition of ROS generation by N-acetylcysteine (NAC) significantly prevented CPO-induced apoptosis. Subsequently, CPO also down-regulated the expression of various downstream gene products that mediate cell proliferation (cyclin D1), survival (bcl-2, bcl-xL, survivin, IAP-1, and IAP-2), metastasis (COX-2), angiogenesis (VEGF), and increased the expression of p53 and p21. Interestingly, we also observed that CPO can significantly potentiate the apoptotic effects of various pharmacological PI3K/AKT inhibitors when employed in combination in tumor cells. Overall, these findings suggest that CPO can interfere with multiple signaling cascades involved in tumorigenesis and used as a potential therapeutic candidate for both the prevention and treatment of cancer. [Copyright &y& Elsevier]

Abstract: Even though embelin, an inhibitor of the XIAP, is known to exhibit anti-inflammatory and anti-cancer activities, very little is known about its mechanism of action. Here, we investigated whether embelin mediates its effect through interference with the signal transducer and activator of transcription 3 (STAT3) pathway. We found that embelin inhibited constitutive STAT3 activation in a variety of human cancer cell lines such as U266, DU-145, and SCC4 cells. The suppression of STAT3 was mediated through inhibition of the activation of JAK2 and c-Src. Pervanadate treatment also reversed the embelin-induced down-regulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that embelin-induced the expression of the tyrosine phosphatase PTEN and deletion of the PTEN gene by small interfering RNA abolished the ability of embelin to inhibit STAT3 activation. Besides, embelin failed to suppress STAT3 activation in PTEN-null PC3 cells, thus indicating that the inhibitory effect of embelin on STAT3 is PTEN-dependent. Embelin down-regulated the expression of STAT3-regulated gene products; this correlated with the suppression of cell proliferation and invasion, and the induction of apoptosis through the activation of caspase-3. Overall, our results indicate that the anti-inflammatory and anti-cancer activities previously assigned to embelin may be mediated in part through the suppression of the STAT3 pathway. [Copyright &y& Elsevier]

Abstract: Although the flavonoid icariside II exhibits anti-inflammatory and anti-cancer activities, its molecular targets/pathways in human multiple myeloma cells are poorly understood. To analyze the effects on signal transducer and activator of transcription 3 (STAT3) signaling and apoptosis, U266 multiple myeloma cells were treated with icariside II and performed Western blotting, electrophoretic mobility gel shift assay (EMSA), RT-PCR, proliferation assay, cell cycle analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Icariside II inhibited STAT3 activation and enhanced the expression of SHP-1 and PTEN through inhibiting Janus activated kinase 2 (JAK2) and c-Src. Icariside II down-regulated the expression of STAT3 target genes Bcl-2, Bcl-xL, survivin, cyclin D1, COX-2 and vascular endothelial growth factor (VEGF). Also, icariside II enhanced poly (ADP-ribose) polymerase (PARP) cleavage and caspase-3 activation. Pervanadate reversed the icariside II-mediated STAT3 inactivation and also blocked the cleavages of caspase-3 and PARP, suggesting involvement of STAT3 pathway in icariside II-induced apoptosis. Furthermore, icariside II enhanced the apoptotic effects of clinically used drugs thalidomide and bortezomib in U266 cells. Icariside II could be a potential therapeutic intervention agent alone or in combination with current drugs for multiple myeloma as a novel blocker of STAT3 signaling cascades at multiple levels, contributing to its anti-proliferative and anti-apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24) is a unique member of the IL-10 gene family that displays nearly ubiquitous cancer-specific toxicity, with no harmful effects toward normal cells or tissues. mda-7/IL-24 was cloned from human melanoma cells by differentiation induction subtraction hybridization (DISH) and promotes endoplasmic reticulum (ER) stress culminating in apoptosis or toxic autophagy in a broad-spectrum of human cancers, when assayed in cell culture, in vivo in human tumor xenograft mouse models and in a Phase I clinical trial in patients with advanced cancers. This therapeutically active cytokine also induces indirect antitumor activity through inhibition of angiogenesis, stimulation of an antitumor immune response, and sensitization of cancer cells to radiation-, chemotherapy- and antibody-induced killing. [ABSTRACT FROM AUTHOR]

Abstract: Expression of astrocyte elevated gene-1 (AEG-1) is elevated in multiple human cancers including brain tumors, neuroblastomas, melanomas, breast cancers, non-small cell lung cancers, liver cancers, prostate cancers, and esophageal cancers. This gene plays crucial roles in tumor cell growth, invasion, angiogenesis and progression to metastasis. In addition, over-expression of AEG-1 protects primary and transformed cells from apoptosis-inducing signals by activating PI3K-Akt signaling pathways. These results suggest that AEG-1 is intimately involved in tumorigenesis and may serve as a potential therapeutic target for various human cancers. However, the normal physiological functions of AEG-1 require clarification. We presently analyzed the expression pattern of AEG-1 during mouse development. AEG-1 was expressed in mid-to-hindbrain, fronto-nasal processes, limbs, and pharyngeal arches in the early developmental period from E8.5 to E9.5. In addition, at stages of E12.5–E18.5 AEG-1 was localized in the brain, and olfactory and skeletal systems suggesting a role in neurogenesis, as well as in skin, including hair follicles, and in the liver, which are organ sites in which AEG-1 has been implicated in tumor development and progression. AEG-1 co-localized with Ki-67, indicating a role in cell proliferation, as previously revealed in tumorigenesis. Taken together, these results suggest that AEG-1 may play a prominent role during normal mouse development in the context of cell proliferation as well as differentiation, and that temporal regulation of AEG-1 expression may be required during specific stages and in specific tissues during development. [ABSTRACT FROM AUTHOR]

Abstract: Tumor progression and metastasis are complex processes involving intricate interplay among multiple gene products. Astrocyte elevated gene (AEG)-1 was cloned as an human immunodeficiency virus (HIV)-1-inducible and tumor necrosis factor-α (TNF-α)-inducible transcript in primary human fetal astrocytes (PHFA) by a rapid subtraction hybridization approach. AEG-1 down-regulates the expression of the glutamate transporter EAAT2; thus, it is implicated in glutamate-induced excitotoxic damage to neurons as evident in HIV-associated neurodegeneration. Interestingly, AEG-1 expression is elevated in subsets of breast cancer, glioblastoma multiforme and melanoma cells, and AEG-1 cooperates with Ha-ras to augment the transformed phenotype of normal immortal cells. Moreover, AEG-1 is overexpressed in >95% of human malignant glioma samples when compared with normal human brain. Overexpression of AEG-1 increases and siRNA inhibition of AEG-1 decreases migration and invasion of human glioma cells, respectively. AEG-1 contains a lung-homing domain facilitating breast tumor metastasis to lungs. These findings indicate that AEG-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers. Our recent observations indicate that AEG-1 exerts its effects by activating the nuclear factor kappa B (NF-κB) pathway and AEG-1 is a downstream target of Ha-ras and plays an important role in Ha-ras-mediated tumorigenesis. These provocative findings are intensifying interest in AEG-1 as a crucial regulator of tumor progression and metastasis and as a potential mediator of neurodegeneration. In this review, we discuss the cloning, structure and function(s) of AEG-1 and provide recent insights into the diverse actions and intriguing properties of this molecule. [Copyright &y& Elsevier]