UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Group B streptococcus (GBS) isolated from human neonates diagnosed with sepsis and respiratory distress produces a polysaccharide exotoxin (CM101) which has been previously described as GBS toxin. CM101 infused i.v. into tumor-bearing mice causes rapid tumor neovascularitis, infiltration of inflammatory cells, inhibition of tumor growth and tumor apoptosis. CM101 has successfully completed phase I studies in refractory cancer patients with very encouraging results. We have now demonstrated a mechanism of action for CM101. Using a normal mouse tumor model, we have examined tumor and normal tissues which were harvested at 0, 5, 15, 30 and 60min post-infusion of either CM101 or dextran. We present evidence that CM101 is rapidly (within the first 5min) bound to the tumor neovasculature. Complement is activated by the alternative pathway (C3) and leukocytes start to infiltrate the tumor within the first 5min. Through RT-PCR and immunohistochemical techniques, we demonstrate that proinflammatory cytokines, interleukin-6 and tumor necrosis factor (TNF)-alpha, are up-regulated in infiltrating leukocytes and TNF receptor 2 is up- regulated in the targeted tumor neovasculature. Combined, these events constitute possible explanations for the observed pathophysiology of tumor ablation.
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PMID:Functional studies on the anti-pathoangiogenic properties of CM101. 1451 62

Chemokines play an important role in leukocyte mobilization, hematopoiesis, and angiogenesis. Tissue-specific expression of particular chemokines also influences tumor growth and metastasis. Here, the CC chemokine pulmonary and activation-regulated chemokine (PARC)/CCL18 was measured in pediatric patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Surprisingly, PARC immunoreactivity was consistently detected in plasma from healthy donors. After purification to homogeneity, the presence of intact PARC (1-69) and processed PARC (1-68) in normal human plasma was confirmed by sequence and mass spectrometry analysis. Furthermore, PARC serum levels were significantly increased in children with T-ALL and prepreB-ALL compared to control serum samples, whereas serum levels in AML and preB-ALL patients were not significantly different from controls. In contrast, the hemofiltrate CC chemokine-1 (HCC-1)/CCL14 was not found to be a biomarker in any of these patients' strata, whereas the cytokine interleukin-6 (IL-6) was significantly decreased in AML and prepreB-ALL. Stimulated leukocytic cell lines or lymphoblasts from patients produced IL-8/CXCL8 or macrophage inflammatory protein-1alpha (MIP-1alpha/CCL3) but not PARC, not even after IL-4 or IL-10 treatment. However, PARC was produced by superantigen or IL-4 stimulated monocytes co-cultured with lymphocytes or lymphoblastic cells. Serum PARC levels thus constitute a novel leukemia marker, possibly reflecting tumor/host cell interactions in the circulation.
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PMID:PARC/CCL18 is a plasma CC chemokine with increased levels in childhood acute lymphoblastic leukemia. 1457 5

In vitro, the human prostate cancer (PCA) cell line LNCaP can be permanently transdifferentiated into a quiescent neuroendocrine (NE) phenotype by the cytokine interleukin-6 (IL-6). Recently, we have shown that the growth of prostate cancer cells is significantly suppressed when cocultured with NE cells. In order to explore the inhibitory activity of IL-6 on prostate tumor growth, nude mice bearing xenografts of the PCA cell lines LNCaP and DU-145 (a line that is incapable of NE transdifferentiation by IL-6 in vitro) were treated with IL-6 for 3 weeks, either injected around the tumor or systematically released from implanted minipumps. Both administration forms of IL-6 inhibited the growth of LNCaP xenografts by more than 75% compared to the control group. In contrast, there was no difference in DU-145 tumor growth between IL-6-treated animals and controls. In comparison to control and DU-145 tumors, both IL-6 injected and pump-infused LNCaP tumors exhibited a significant increase in the expression of the NE markers neuron-specific enolase (NSE) and betaIII tubulin. Serum NSE levels were also significantly elevated in both IL-6-treated LNCaP tumor groups when compared to controls. IL-6 treatment resulted in G(0) cell cycle accumulation as evidenced by a loss of Ki-67 expression in > 90% of LNCaP tumor cells. These combined results demonstrate that IL-6-induced NE transdifferentiation of PCA cells has a significant inhibitory effect on tumor growth in mice. Agents, like IL-6, capable of NE transdifferentiation of PCA cells, should be considered as a new therapeutic approach for the treatment of prostate cancer.
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PMID:Interleukin-6 inhibits the growth of prostate cancer xenografts in mice by the process of neuroendocrine differentiation. 1523 27

In this study, we investigated the in vitro and in vivo efficacy of patupilone (epothilone B, EPO906), a novel nontaxane microtubule stabilizing agent, in treatment of multiple myeloma (MM). Patupilone directly inhibited growth and survival of MM cells, including those resistant to conventional chemotherapies, such as the taxane paclitaxel. Patupilone induced G2M arrest of MM cells, with subsequent apoptosis. Interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1), 2 known growth and survival factors for MM, did not protect MM.1S cells against patupilone-induced cell death. Proliferation of MM cells induced by adherence to bone marrow stromal cells (BMSCs) was also inhibited by patupilone and was paralleled by down-regulation of vascular endothelial growth factor (VEGF) secretion. Importantly, stimulation of cells from patients with MM, either with IL-6 or by adherence to BMSCs, enhanced the anti-proliferative and proapoptotic effects of patupilone. Moreover, patupilone was effective against MM cell lines that overexpress the MDR1/P-glycoprotein multidrug efflux pump. In addition, patupilone was effective in slowing tumor growth and prolonging median survival of mice that received orthotopical transplants with MM tumor cells. Taken together, these preclinical findings suggest that patupilone may be a safe and effective drug in the treatment of MM, providing the framework for clinical studies to improve patient outcome in MM.
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PMID:Patupilone (epothilone B) inhibits growth and survival of multiple myeloma cells in vitro and in vivo. 1536 26

Host-tumor interactions in uveal melanoma are not well understood. It is believed that the cytokine interleukin-6 and the lipid mediator autacoid prostaglandin E2 are involved in tumor growth, proliferation, tumor cell survival, and angiogenesis. These cytokines have been shown to be poor prognostic markers in uveal and cutaneous melanoma. In this study, we investigated the levels of interleukin-6 and prostaglandin E2 in monocyte and uveal melanoma conditioned medium. Five human uveal melanoma cell lines (92.1, MKT-BR, OCM-1, SP6.5 and UW-1), and one monocyte cell line (28SC) were seeded in 6 well plates at a concentration of 1 x 10(6)cells ml(-1). After 18 hr melanoma conditioned medium was placed on the monocyte cell line and monocyte conditioned medium was placed on each uveal melanoma cell line. Tumor cells and monocytes incubated in fresh medium after 18 hr were used as controls. Interleukin-6 and prostaglandin E2 levels were determined by immunoassays prior to media transfer and 6, 12, 24, and 36 hr thereafter. In the absence of conditioned medium, neither product showed baseline levels of expression. Interleukin-6 but not prostaglandin E2, which remained undetectable for the duration of the study, showed up-regulation of expression after incubation in conditioned medium. 28SC incubated in melanoma conditioned medium expressed higher levels of interleukin-6 than did uveal melanoma cells incubated in monocyte conditioned medium. In addition each cell line exhibited a distinct pattern of expression with individual cell lines exhibiting peak levels of cytokine production at different time points. The results of this study offer insight into the mechanism by which interleukin 6 may be involved in tumor-host interactions potentially favoring tumor growth, survival, and proliferation.
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PMID:Secretion of interleukin-6 and prostaglandin E2 during uveal melanoma-monocyte in vitro interactions. 1538 Oct 29

The aberrant behavior of cancer reflects upregulation of certain oncogenic signaling pathways that promote proliferation, inhibit apoptosis, and enable the cancer to spread and evoke angiogenesis. Theoretically, it should be feasible to decrease the activity of these pathways-or increase the activity of pathways that oppose them-with noncytotoxic agents. Since multiple pathways are dysfunctional in most cancers, and cancers accumulate new oncogenic mutations as they progress, the greatest and most durable therapeutic benefit will likely be achieved with combination regimens that address several targets. Thus, a multifocal signal modulation therapy (MSMT) of cancer is proposed. This concept has already been documented by researchers who have shown that certain combinations of signal modulators-of limited utility when administered individually-can achieve dramatic suppression of tumor growth in rodent xenograft models. The present essay attempts to guide development of MSMTs for prostate cancer. Androgen ablation is a signal-modulating measure already in standard use in the management of delocalized prostate cancer. The additional molecular targets considered here include the type 1 insulin-like growth factor receptor, the epidermal growth factor receptor, mammalian target of rapamycin, NF-kappaB, hypoxia-inducible factor-1alpha, hsp90, cyclooxygenase-2, protein kinase A type I, vascular endothelial growth factor, 5-lipoxygenase, 12-lipoxygenase, angiotensin II receptor type 1, bradykinin receptor type 1, c-Src, interleukin-6, ras, MDM2, bcl-2/bclxL, vitamin D receptor, estrogen receptor-beta, and PPAR-. Various nutrients and phytochemicals suspected to have potential utility in prostate cancer prevention and therapy, but whose key molecular targets are still unknown, might reasonably be incorporated into MSMTs for prostate cancer; these include lycopene, selenium, green tea polyphenols, genistein, and silibinin. MSMTs can be developed systematically by testing various combinations of signal-modulating agents, in concentrations that can feasibly be achieved and maintained clinically, on human prostate cancer cell lines; combinations that appear promising can then be tested in xenograft models and, ultimately, in the clinic. Some signal modulators can increase response to cytotoxic drugs by upregulating effectors of apoptosis. When MSMTs fail to raise the spontaneous apoptosis rate sufficiently to achieve tumor stasis or regression, incorporation of appropriate cytotoxic agents into the regimen may improve the clinical outcome.
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PMID:Targeting multiple signaling pathways as a strategy for managing prostate cancer: multifocal signal modulation therapy. 1552 6

Approximately 60% of all breast tumors are estrogen-responsive and chemicals that show estrogenic or anti-estrogenic properties are able to interact with breast tumor growth. In a breast tumor, adipose stromal cells (fibroblasts) surrounding the epithelial tumor contain the aromatase enzyme, which converts androgens into estrogens. Exposure to aromatase inducers can therefore lead to increased estrogen levels and possibly to accelerated breast tumor growth. Subsequently, breast tumor cells synthesize and secrete elevated levels of factors such as prostaglandin E2 (PGE2), interleukin-6 (IL-6), and IL-6 soluble receptor (IL-6sR), which in turn have the ability to stimulate aromatase gene transcription in fibroblasts, establishing a positive feedback loop. In this study, a technique that allows for culturing MCF-7 epithelial breast tumor cells and healthy primary human mammary fibroblasts together in one compartment was developed. To establish the positive feedback loop, the co-culture was exposed to estrogenic compounds. RNA was isolated and reverse-transcriptase polymerase chain reaction (RT-PCR) was performed on the aromatase and pS2 genes. Exposure of the co-culture to estradiol (E2), diethylstilbestrol (DES), and bisphenol-A (BPA), resulted in a three- to seven-fold increase of pS2 transcription levels. Furthermore, pS2 transcription levels increased even more when the aromatase substrate testosterone (20 nM) was present in the co-culture medium. Exposure of the co-culture to the aromatase inducer dexamethasone (DEX) resulted in increased pS2 transcription levels, as well as increased aromatase transcription levels. Simultaneous exposure to DEX and the synthetic anti-estrogen ICI 182,780 almost completely blocked the pS2 response. The aromatase induction response was not altered by ICI 182,780 treatment. Simultaneous exposure to DEX and the non-steroidal aromatase inhibitor fadrozole, abolished the effect of the presence of testosterone in the co-culture medium, but did not result in pS2 gene transcription levels as low as seen after exposure to ICI 182,780. These observations indicate the presence of a positive feedback loop in our co-culture system. This co-culture provides a more sophisticated and sensitive system to detect direct and indirect estrogenic effects of compounds and their possible effects on breast tumor promotion.
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PMID:Co-culture of primary human mammary fibroblasts and MCF-7 cells as an in vitro breast cancer model. 1552 92

Tumor cell lines are relied on extensively for cancer investigations, yet cultured cells in an in vitro environment differ considerably in behavior compared with those of the same cancer cells that proliferate and form tumors in vivo. To uncover gene expression changes related to tumor formation, gene expression profiles of human lung adenocarcinoma (A549) cells grown as lung tumors in immune-compromised mice were compared with profiles of the same cells grown in vitro. Additionally, profiles of uninvolved adjacent mouse tissue were determined. A profound interplay between cancer cells and the host was shown that affected a complex protein interaction network involving processes of extracellular interaction, growth factor signaling, hemostasis, immune response, and transcriptional regulation. Growth in vivo of A549 cells, which carry an activating k-ras mutation, induced changes in gene expression that corresponded highly to a pattern characteristic of human lung tumors with k-ras mutation. Cytokines interleukin-4, interleukin-6, and IFN-gamma each induced distinct in vitro genomic responses in cancer cells that emulated many of the changes in gene expression observed in vivo. Genes that were both selectively induced in vivo and overexpressed in human lung adenocarcinoma tumors included CSPG2, which has not been associated previously with tumor formation. Knockdown in A549 of CSPG2 by RNA interference significantly inhibited tumor growth in vivo but not in vitro. Thus, analysis of tumor xenografts by gene expression profiling has the potential for identifying genes involved in tumor development that may not be expressed in cancer cells grown in vitro.
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PMID:Analysis of tumor-host interactions by gene expression profiling of lung adenocarcinoma xenografts identifies genes involved in tumor formation. 1579 92

Interleukin-6 (IL-6) protects multiple myeloma cells against apoptosis induced by glucocorticoids. Here, we investigated whether inhibition of the IL-6 signaling pathway by the IL-6 receptor superantagonist Sant7 enhances the in vivo antitumor effects of dexamethasone on the IL-6-dependent multiple myeloma cell line INA-6. For this purpose, we used a novel murine model of human multiple myeloma in which IL-6-dependent INA-6 multiple myeloma cells were directly injected into human bone marrow implants in severe combined immunodeficient (SCID) mice (SCID-hu). The effect of in vivo drug treatments on multiple myeloma cell growth was monitored by serial determinations of serum levels of soluble IL-6 receptor (shuIL-6R), which is released by INA-6 cells and served as a marker of tumor growth. In SCID-hu mice engrafted with INA-6 cells, treatment with either Sant7 or dexamethasone alone did not induce significant reduction in serum shuIL-6R levels. In contrast, the combination of Sant7 with dexamethasone resulted in a synergistic reduction in serum shuIL-6R levels after 6 consecutive days of treatment. Gene expression profiling of INA-6 cells showed down-regulation of proliferation/maintenance and cell cycle control genes, as well as up-regulation of apoptotic genes in multiple myeloma cells triggered by Sant7 and dexamethasone combination. In vitro colony assays showed inhibition of myeloid and erythroid colonies from normal human CD34(+) progenitors in response to dexamethasone, whereas Sant7 neither inhibited colony growth nor potentiated the inhibitory effect of dexamethasone. Taken together, these results indicate that inhibition of IL-6 signaling by Sant7 significantly potentiates the therapeutic action of dexamethasone against multiple myeloma cells, providing the preclinical rationale for clinical trials of Sant7 in combination with dexamethasone to improve patient outcome in multiple myeloma.
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PMID:Combination therapy with interleukin-6 receptor superantagonist Sant7 and dexamethasone induces antitumor effects in a novel SCID-hu In vivo model of human multiple myeloma. 1593 Mar 64

The signal pathways that trigger tumor cell escape from immune surveillance are incompletely understood. Toll-like receptors (TLRs), which activate innate and adaptive immune responses, are thought to be restricted to immune cells. We show here that TLRs, including TLR4, are expressed on tumor cells from a wide variety of tissues, suggesting that TLR activation may be an important event in tumor cell immune evasion. Activation of TLR4 signaling in tumor cells by lipopolysaccharide induces the synthesis of various soluble factors and proteins including interleukin-6, inducible nitric oxide synthase, interleukin-12, B7-H1, and B7-H2, and results in resistance of tumor cells to CTL attack. In addition, lipopolysaccharide-stimulated tumor cell supernatants inhibit both T cell proliferation and natural killer cell activity. Blockade of the TLR4 pathway by either TLR4 short interfering RNA or a cell-permeable TLR4 inhibitory peptide reverses tumor-mediated suppression of T cell proliferation and natural killer cell activity in vitro, and in vivo, delays tumor growth and thus prolongs the survival of tumor-bearing mice. These findings indicate that TLR signaling results in a cascade leading to tumor evasion from immune surveillance. These novel functions of TLRs in tumor biology suggest a new class of therapeutic targets for cancer therapy.
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PMID:Toll-like receptors on tumor cells facilitate evasion of immune surveillance. 3141 49

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