Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protein kinases represent promising anticancer drug targets. We describe here the meriolins, a new family of inhibitors of cyclin-dependent kinases (CDK). Meriolins represent a chemical structural hybrid between meridianins and variolins, two families of kinase inhibitors extracted from various marine invertebrates. Variolin B is currently in preclinical evaluation as an antitumor agent. A selectivity study done on 32 kinases showed that, compared with variolin B, meriolins display enhanced specificity toward CDKs, with marked potency on CDK2 and CDK9. The structures of pCDK2/cyclin A/variolin B and pCDK2/cyclin A/meriolin 3 complexes reveal that the two inhibitors bind within the ATP binding site of the kinase, but in different orientations. Meriolins display better antiproliferative and proapoptotic properties in human tumor cell cultures than their parent molecules, meridianins and variolins. Phosphorylation at CDK1, CDK4, and CDK9 sites on, respectively, protein phosphatase 1alpha, retinoblastoma protein, and RNA polymerase II is inhibited in neuroblastoma SH-SY5Y cells exposed to meriolins. Apoptosis triggered by meriolins is accompanied by rapid Mcl-1 down-regulation, cytochrome c release, and activation of caspases. Meriolin 3 potently inhibits tumor growth in two mouse xenograft cancer models, namely, Ewing's sarcoma and LS174T colorectal carcinoma. Meriolins thus constitute a new CDK inhibitory scaffold, with promising antitumor activity, derived from molecules initially isolated from marine organisms.
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PMID:Meriolins, a new class of cell death inducing kinase inhibitors with enhanced selectivity for cyclin-dependent kinases. 1780 48

The NF-AT transcription factors regulated by the phosphatase calcineurin play a role in breast cancer metastasis-promoting tumor cell invasion. Metastasis is a multistep process requiring angiogenesis and endothelial activation. NF-AT is also expressed in endothelial cells, and calcineurin-NF-AT signaling is an important downstream effector of the proangiogenic cytokine VEGF. One isoform of the endogenous calcineurin regulator, Down syndrome candidate region-1 (DSCR1.Ex4), suppresses calcineurin-NFAT signaling blocking endothelial proliferation. However, overexpression of the other DSCR1 isoform (DSCR1.Ex1) may promote angiogenesis. We report that targeted deletion of both isoforms leads to hyperactivated calcineurin and precocious endothelial apoptosis, inhibiting formation of an effective tumor vasculature and suppressing tumorigenesis. Treatment with the specific pharmacological calcineurin inhibitor cyclosporin A rescues this endothelial defect in DSCR1(-/-) mice, restoring tumor growth.
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PMID:Targeted deletion of the calcineurin inhibitor DSCR1 suppresses tumor growth. 1845 25

Cancer is an increasing and major problem after solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors. We propose that the effect of calcineurin inhibitors on the expression of vascular endothelial growth factor (VEGF) leads to an angiogenic milieu that favors tumor growth. Here, we used 786-0 human renal cancer cells to investigate the effect of cyclosporine (CsA) on VEGF expression. Using a full-length VEGF promoter-luciferase construct, we found that CsA markedly induced VEGF transcriptional activation through the protein kinase C (PKC) signaling pathway, specifically involving PKC zeta and PKC delta isoforms. Moreover, CsA promoted the association of PKC zeta and PKC delta with the transcription factor Sp1 as observed by immunoprecipitation assays. Using promoter deletion constructs, we found that CsA-mediated VEGF transcription was primarily Sp1 dependent. Furthermore, CsA-induced and PKC-Sp1-mediated VEGF transcriptional activation was partially inhibited by von Hippel-Lindau protein. CsA also promoted the progression of human renal tumors in vivo, wherein VEGF is overexpressed. Finally, to evaluate the in vivo significance of CsA-induced VEGF overexpression in terms of post-transplantation tumor development, we injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully MHC mismatched cardiac transplants. We observed that therapeutic doses of CsA increased tumor size and VEGF mRNA expression and also enhanced tumor angiogenesis. However, coadministration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. Collectively, these findings define PKC-mediated VEGF transcriptional activation as a key component in the progression of CsA-induced post-transplantation cancer.
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PMID:Overexpression of vascular endothelial growth factor and the development of post-transplantation cancer. 1863 21

Recent improvements in immunosuppressive therapies have reduced the incidence of acute rejection and increased patient survival. These agents may however contribute to higher rates of mortality due to an increased risk of cardiovascular disease or malignancy. Transplant patients are immunocompromised with a reduced ability to combat the development of malignancy. The higher risk for the activity of oncoviruses may also contribute to the higher incidence and determine specific tumor types. Some immunosuppressants seem to have direct oncogenic effects. In vitro data have demonstrated that calcineurin inhibitors (CNIs) may show direct effects on tumor growth and the development of metastases. In contrast, mTOR inhibitors have demonstrated anti-tumoral properties in vitro and perhaps potent anti-angiogenic effects thereby. Recent studies and registry analyses have confirmed that mTOR inhibitors are associated with a reduced incidence of malignancies. UNOS data demonstrated that an mTOR inhibitor, with or without a CNI, is associated with a reduced incidence of tumors compared to regimens without mTOR inhibitors. The Rapamune Maintenance Regimen study demonstrated that patients receiving sirolimus-based, CNI-free therapy after CsA withdrawal at 3 months showed a reduced incidence of malignancy at 5 years posttransplant, compared with those who continued on a regimen that included CsA. In the CONVERT study, patients converted to sirolimus revealed a significantly lower malignancy rate at 24 months (3.1%) compared with those who continued CNI-based therapy (9.8%, P < .001). The elimination of CNIs and the introduction of sirolimus may, therefore, have a role to reduce the risk of cancer among posttransplant patients.
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PMID:Minimizing the risk of posttransplant malignancy. 1910 Sep 6

Deregulation of the cell cycle has long been recognized as an essential driver of tumorigenesis, and agents that selectively target key cell cycle components continue to hold promise as potential therapeutics. We have developed AZD5438, a 4-(1-isopropyl-2-methylimidazol-5-yl)-2-(4-methylsulphonylanilino) pyrimidine, as a potent inhibitor of cyclin-dependent kinase (cdk) 1, 2, and 9 (IC(50), 16, 6, and 20 nmol/L, respectively). In vitro, AZD5438 showed significant antiproliferative activity in human tumor cell lines (IC(50) range, 0.2-1.7 micromol/L), causing inhibition of the phosphorylation of cdk substrates pRb, nucleolin, protein phosphatase 1a, and RNA polymerase II COOH-terminal domain and blocking cell cycling at G(2)-M, S, and G(1) phases. In vivo, when orally administered at either 50 mg/kg twice daily or 75 mg/kg once daily, AZD5438 inhibited human tumor xenograft growth (maximum percentage tumor growth inhibition, range, 38-153; P < 0.05). In vivo, AZD5438 reduced the proportion of actively cycling cells. Further pharmacodynamic analysis of AZD5438-treated SW620 xenografts showed that efficacious doses of AZD5438 (>40% tumor growth inhibition) maintained suppression of biomarkers, such as phospho-pRbSer(249)/Thr(252), for up to 16 hours following a single oral dose. A comparison of different schedules indicated that chronic daily oral dosing provided optimal cover to ensure antitumor efficacy. These data indicate that broad cdk inhibition may provide an effective method to impair the dysregulated cell cycle that drives tumorigenesis and AZD5438 has the pharmacologic profile that provides an ideal probe to test this premise.
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PMID:AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. 1950 70

Macrophages infiltrating solid tumors exhibit a tumor-supporting phenotype and are critical for tumor development. Little is known which tumor-derived signal provokes this phenotype shift and how these signals are interpreted in macrophages to support tumor growth. We used the supernatant of apoptotic cells and noticed transcriptional, nuclear factor of activated T cells-dependent up-regulation of hypoxia-inducible factor (HIF)-1alpha mRNA, subsequent protein expression, and HIF-1 activity. Blocking calcineurin with cyclosporine A attenuated nuclear factor of activated T cells binding during electrophoretic mobility shift assay analysis and circumvented the HIF-1alpha mRNA increase. Knockdown experiments, receptor analysis, and antibody neutralization pointed to sphingosine-1-phosphate and transforming growth factor-beta as the initiators of the HIF-1 response. The use of macrophages from conditional HIF-1alpha knockout mice revealed that macrophages, under the impact of apoptotic cell supernatants, use HIF-1 to produce factors that induce CD31 expression in murine embryonic stem cells. Our study supports the notion that soluble factors produced from apoptotic tumor cells activate the HIF-1 system under normoxia in macrophages to enhance their tumor-promoting capacity by, for example, releasing vascular endothelial growth factor. This shows the importance of HIF-1-elicited responses in regulatory macrophages under normoxia.
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PMID:The supernatant of apoptotic cells causes transcriptional activation of hypoxia-inducible factor-1alpha in macrophages via sphingosine-1-phosphate and transforming growth factor-beta. 1954 90

Glioblastoma multiforme (GBM) is the most frequent and incurable type of brain tumor of adults. Hypoxia has been shown to direct GBM toward a more aggressive and malignant state. Here we show that hypoxia increases Notch1 activation, which in turn induces the expression of transient receptor potential 6 (TRPC6) in primary samples and cell lines derived from GBM. TRPC6 is required for the development of the aggressive phenotype because knockdown of TRPC6 expression inhibits glioma growth, invasion, and angiogenesis. Functionally, TRPC6 causes a sustained elevation of intracellular calcium that is coupled to the activation of the calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Pharmacologic inhibition of the calcineurin-NFAT pathway substantially reduces the development of the malignant GBM phenotypes under hypoxia. Clinically, expression of TRPC6 was elevated in GBM specimens in comparison with normal tissues. Collectively, our studies indicate that TRPC6 is a key mediator of tumor growth of GBM in vitro and in vivo and that TRPC6 may be a promising therapeutic target in the treatment of human GBM.
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PMID:Receptor channel TRPC6 is a key mediator of Notch-driven glioblastoma growth and invasiveness. 2002 70

The high incidence of cancer and its aggressive progression is a common and major problem in patients receiving immunosuppressive therapy. The calcineurin inhibitors (CNIs) may have protumorigenic effects and can promote the overexpression of several molecules inducing tumor growth. We have recently demonstrated that CNIs can mediate the transcriptional activation of the angiogenic cytokine vascular endothelial growth factor (VEGF) and promote a rapid progression of human renal cancer. Here, we investigated whether the CNI cyclosporine (CsA) and the mTOR inhibitor rapamycin (RAPA) could alter the mRNA stability of VEGF in 786-0 and Caki-1 renal cancer cells. Following actinomycin D treatment, we observed that CsA increased, whereas RAPA decreased the VEGF mRNA stability as observed by real time PCR. It is established that the mRNA-binding protein HuR may play a critical role in VEGF mRNA stability. By using HuR-siRNA, we found that the knockdown of HuR significantly decreased the CNI-induced VEGF mRNA stability. By Western blot analysis, it has been observed that CNI treatment induced the translocation of HuR from the nucleus to the cytoplasm; CNIs also induced the association between HuR and PKC-delta and promoted the phosphorylation of HuR. Finally, we found that the inhibition of PKC-delta using a dominant negative plasmid significantly decreased the CsA-induced cytoplasmic translocation of HuR and VEGF mRNA stability. Together, targeting the pathways that promote CNI-induced transcription as well as the mRNA stability of VEGF might serve as novel therapeutics for the prevention and treatment of cancer in immunosuppressed patients.
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PMID:Altered VEGF mRNA stability following treatments with immunosuppressive agents: implications for cancer development. 2055 20

Recent improvements in immunosuppressive therapies have reduced the incidence of acute rejection and increased patient survival. These agents may however contribute to higher rates of mortality due to an increased risk of cardiovascular disease or malignancy. Transplant patients are in an immunocompromised state, and have a reduced ability to combat the development of malignancy. The higher risk for the activity of oncoviruses may also contribute to the higher incidence and the specific tumor types seen. Some immunosuppressants may have a direct oncogenic effect. In vitro data have demonstrated that calcineurin inhibitors (CNIs) may have a direct effect on tumor growth and the development of metastases. In contrast, mTOR inhibitors have demonstrated in vitro antitumoral properties, perhaps via a potent antiangiogenic effect. Recent studies and registry analyses have confirmed that mTOR inhibitors are associated with a reduced incidence of malignancies. UNOS data demonstrated that an mTOR inhibitor, with or without a CNI, is associated with a reduced incidence of cancer compared to regimens without mTOR inhibitors. The Rapamune Maintenance Regimen study demonstrated that patients receiving sirolimus-based, CNI-free therapy after CsA withdrawal at 3 months had a reduced incidence of malignancy at 5 years post-transplant compared with those who continued a regimen including CsA. In the CONVERT study, patients converted to sirolimus had significantly lower malignancy rates (3.1%) at 24 months compared with those who continued CNI-based therapy (9.8%, p<0.001). The elimination of CNIs and the introduction of sirolimus may therefore have a role in reducing the risk of cancer in post-transplant patients.
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PMID:[Minimizing the risk of cancer in transplant patients]. 2092 1

The risk of renal transplant recipients developing a malignancy is increasingly recognized as a major issue impacting long-term overall survival. As immunosuppression is thought to contribute to the development of cancer but is therapeutically required to protect against kidney rejection, reducing cancer in this setting is a challenging objective. An important question is whether there is a selective difference between pharmacological immunosuppressants regarding effects on malignancy. Both experimental and clinical studies thus far suggest that calcineurin inhibitors tend to promote tumor development; mycophenolic acid prodrugs such as mycophenolate mofetil have exhibited some capacity to inhibit tumors, but the concentrations needed for this effect are well above levels sustainable in transplant recipients. In contrast to these immunosuppressive substances, despite its potent immunosuppressive effects, rapamycin has demonstrated an impressive ability to inhibit de novo tumor development, as well as reduce tumor growth once cancer is already established. The antitumor effects of rapamycin are being studied extensively and appear to stem from the central role that the mammalian target of rapamycin molecule plays in basic cellular processes such as cell growth and proliferation, which are also essential for neoplasm development. Pilot trials and retrospective analyses of clinical data, especially using sirolimus, are highly suggestive that rapamycin can inhibit tumors in the clinical transplant setting. Prospective clinical trials are currently underway that will bring definitive answers as to whether rapamycin treatment can act simultaneously as an immunosuppressive and anticancer agent, with the aim of reducing the long-term problem of posttransplant malignancy.
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PMID:Can immunosuppressive strategies be used to reduce cancer risk in renal transplant patients? 2109 49


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