Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598934 (tumor growth)
 58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intracellular accumulation of cAMP inhibits the growth of transformed cells in vitro and in vivo, and exposure to various cAMP analogs produces similar results. The influence of such analogs on the growth of neoplastic cells in vivo is less well defined, and the relevance of these analogs for the phosphoinositide pathway has not been established. The present report details the inhibition of tumor growth that occurred when human mammary xenografts were treated with 8-Cl-cAMP, the subsequent rebound in tumor growth that occurred when treatment ceased, and the levels of diacylglycerol and membrane-associated protein kinase C activity that characterized tumors in different growth states. Tumor levels of diacylglycerol and particulate PKC activity appeared to be influenced not only by treatment but also by treatment withdrawal. Changes in these entities tended to coincide with tumor growth rate, being relatively suppressed during growth stasis and markedly elevated during periods of rapid growth. The data presented do not establish a causal relationship. Thus, the concomitant changes noted in tumor growth and tumor levels of either diacylglycerol and membrane-associated protein kinase C may only be coincidental. Alternatively, they may indicate that cAMP analogs inhibit tumor growth in vivo by modulating the phosphoinositide pathway.
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PMID:Changes in diacylglycerol and membrane associated protein kinase C activity reflect the growth status of xenografted human mammary carcinoma treated with 8-Cl-cAMP. 231 79

Phorbol ester tumor promoter treatment produced a biphasic effect on the binding of polyclonal whole-serum natural antibody (NAb) by L5178Y-F9 murine lymphoma cells. In vitro tumor growth in 100 ng/ml 12-O-tetradecanoylphorbol-13-acetate (TPA) produced a rapid decrease followed by a reversible and unstable increase in NAb binding detected at 4 degrees C. The latter was associated with a functional decrease in NAb binding at 37 degrees C and increases in the tumorigenic and metastatic potentials in vivo. Colchicine, cytochalasin B and sodium azide inhibited the NAb binding of TPA-treated cells, while only colchicine reduced the binding of controls, suggesting the dependence of the TPA-induced increase in NAb binding on microfilament organization and active energy production. The non-tumor-promoting, non-PKC-activating TPA analogue 4-O-Me-TPA failed to alter NAb binding, arguing against nonspecific effects of TPA. The non-tumor-promoting, PKC-activating diacylglycerol, OAG, reproduced the initial decrease in NAb binding but was unable to mimic the subsequent TPA-induced increase. The PKC inhibitor H-7, but not HA1004, could block the TPA-induced increase in NAb binding. Together the data argue that PKC activation is required for both TPA-induced changes in NAb binding but that it is not sufficient to generate the energy- and microfilament-system-dependent, unstable high-NAb-binding phenotype associated with increased tumor progression.
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PMID:Phorbol ester tumor promoter regulation of natural antitumor antibody binding depends on protein kinase C and an intact microfilament system. 789 3

Murine macrophages respond to endotoxins by inducing a vast array of genes that play a major role in the host's response to infection and tumor growth. We have isolated and characterized a 1.8-kb cDNA, designated IRG2, from a cDNA library prepared from RNA isolated from the murine cell line, RAW 264.7, after bacterial LPS stimulation. The cDNA encodes a protein of 47 kDa that is the murine homologue of a small family of proteins described from IFN-induced human cells. The IRG2 message does not appear until 3 h after LPS exposure and its induction is dependent on new protein synthesis. IRG2 induction by LPS is slightly inhibited by the anti-inflammatory steroid, dexamethasone. Increasing cytosolic cAMP with either forskolin, dibutyryl cAMP, or 8-(4-chlorophenylthio)-cAMP caused marked inhibition of the LPS induction of IRG2. In contrast, activation of PKC with phorbol ester potentiated the LPS response. Removing extracellular Ca2+ with EGTA inhibited IRG2 induction; increasing intracellular calcium with the calcium ionophore A23187 led to enhanced levels of the IRG2 transcript. These data suggest that the induction of IRG2 occurs via a PKC pathway.
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PMID:Molecular cloning and characterization of a murine LPS-inducible cDNA. 820 6

Glioblastoma multiforme is the most common form of malignant brain cancer in adults and, unfortunately, is not amenable to treatment with current therapeutic modalities. Human glioblastoma U-87 has many of the distinguishing phenotypic features of primary glioblastoma, including an autocrine form of proliferation, high levels of protein kinase C alpha (PKC alpha), and infiltration via white matter tracts. We show that treatment of mice bearing U-87 xenografts with an antisense phosphorothioate oligodeoxynucleotide (S-oligodeoxynucleotide) against the 3'-untranslated region of PKC alpha mRNA results in suppression of tumor growth. Growth was inhibited in both subcutaneous and intracranial tumors, and in the latter instance, treatment with the antisense PKC alpha S-oligodeoxynucleotide resulted in a doubling in median survival time ( > 80 days), with 40% long term survivors. The antisense S-oligodeoxynucleotide did not produce systemic toxicity in mice with subcutaneous or intracranial tumors after daily intraperitoneal injection for 21 or 80 days, respectively, and a scrambled S-oligodeoxynucleotide with the same nucleotide composition as the antisense S-oligodeoxynucleotide did not produce an antitumor effect. The intratumoral levels of both antisense and scrambled S-oligodeoxynucleotide in subcutaneous tumors were 2 microM after 21 daily doses of 20 mg/kg S-oligodeoxynucleotide. The antisense S-oligodeoxynucleotide selectively reduced the levels of PKC alpha in subcutaneous tumors but not those of protein kinase C epsilon or protein kinase C zeta. This is the first demonstration that the growth of glioblastoma multiforme can be suppressed by an antisense PKC alpha S-oligodeoxynucleotide and suggests that this may represent an effective therapy for this type of malignancy.
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PMID:Treatment of glioblastoma U-87 by systemic administration of an antisense protein kinase C-alpha phosphorothioate oligodeoxynucleotide. 870 Jan 29

We investigated the cleavage activity, stability, and efficacy of 2'-amino pyrimidine modified ribozymes on malignant glioma growth. A synthetic protein kinase C alpha (PKC alpha) ribozyme with complete pyrimidine nucleotide substitution retained a comparable cleavage activity compared with the unmodified ribozyme. The half-life of the modified ribozyme in serum was increased 14,000-fold compared with the unmodified version. The PKC alpha modified ribozyme inhibited glioma cell growth in vitro as a result of the inhibition of PKC alpha gene expression. A single injection of cationic liposome ribozyme complexes into glioma tumors inhibited tumor growth, demonstrating both the efficacy of the ribozyme and a major role of PKC alpha in tumor growth.
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PMID:A nuclease-resistant protein kinase C alpha ribozyme blocks glioma cell growth. 962 87

Suppressor macrophages induced by the continuous invasion of tumor cells and parasites, which can acquire an ability in vitro to kill or inhibit tumor cells and inhibit the activity of T, B lymphocytes and NK cells, have been indicated. We have developed a procedure previously to modulate the suppressor macrophages by bacterial lipopolysaccharide (LPS). The modulated macrophages remained and even enhanced the ability to inhibit tumor growth and to up-regulate or enhance the activities of T, B lymphocytes and NK cells in vitro. However, the mechanisms of macrophage modulation by LPS are unknown. This investigation was designed to analyze the regulation of PKC activity and to characterize the isoforms of PKC during macrophage modulation by using Western blot and endogenous substrate phosphorylation (PKC-DESP). In rest cells, PKC-beta was found to be the most abundant isoform in macrophages; and PKC-alpha, beta was found predominantly in the cytosol. Using PMA as a positive control, we found that the immuno-modulator agent--LPS triggered the physical translocation from the cytosol onto the membrane of PKC-alpha and PKC-epsilon, but PKC-beta (beta I or beta II) was difficult to detect. The analysis of PKC-DESP showed a pattern with a time course similar to that observed with Western blot. We observed that LPS and PMA increase the level of phosphorylation of 55 kDa and 74 kDa proteins with a corresponding decrease in the cytosolic proteins. It suggests that the translocation of PKC-alpha and PKC-epsilon, may be important events involving in the PKC-pathway by LPS-mediated modulation in suppressor macrophages.
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PMID:[LPS and PMA induced PKC-alpha and PKC-epsilon activation and translocation in murine peritoneal macrophages]. 977 87

We have evaluated the effects of bryostatin 1 on growth of a highly malignant p53-null mouse mammary tumor line, 4T1, and the mechanism by which bryostatin 1 inhibits in vitro growth and in vivo development of tumor and metastases from the orthotopic site. Bryostatin 1 at 20-400 nM concentrations inhibits growth of 4T1 cells by approximately 60% in two-day cultures. Inhibition of growth is associated with an increase in the number of cells undergoing apoptosis with concomitant elevation in the steady state levels of bax protein and drop in bcl-2 levels. The cytotoxic effect of bryostatin 1 on 4T1 cells occurs independently of p53, since there was no evidence of p53-mediated transcriptional activity in 4T1 cells following treatment with bryostatin 1.4T1 cells respond in vivo to bryostatin 1 therapy (75 microg/kg body weight). Intraperitoneal administration of bryostatin 1 inhibits both primary and secondary tumor growth by approximately 50%. However, although bryostatin 1 has a remarkable capacity to slow tumor growth and progression, it is unable to completely eradicate tumor growth and progression due to in vivo development of tumor resistance to bryostatin 1. Levels and cellular distribution of PKCalpha and delta do not correlate with the growth inhibitory effects of bryostatin 1 on 4T1 cells; however, reduction in cytosolic PKCalpha and delta without associated increase in membrane compartment appear to correlate with bryostatin-resistance. Our results suggest that the therapeutic effects of bryostatin 1 in our system do not involve alterations in levels and distribution of PKC but rather a direct upregulation of bax/ bcl-2 ratios that is independent of p53.
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PMID:p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity. 985 25

Although clonogenic or divisional death is the main mechanism by which DNA-damaging agents demonstrate antitumor activity, recent data indicate that strategies specifically designed to trigger apoptosis may also prove to be useful antitumor agents. Protein kinase C (PKC) isoenzymes are involved in the regulation of cell proliferation, differentiation, and survival. Whereas pharmacological inhibition of PKC activity triggers apoptosis in most mammalian cells, cell line and tissue differences in sensitivities to these inhibitors remain. Whereas PKC inhibitors have potential as antitumor agents, issue of kinase specificity and solubility have remained obstacles to their clinical use. In this report, we investigated the antitumor activity of the PKC inhibitor chelerythrine chloride (chelerythrine), a selective inhibitor of group A and B PKC isoforms. Chelerythrine exhibited cytotoxic activity against nine human tumor cell lines tested in vitro. On the basis of the finding that radioresistant and chemoresistant squamous cell carcinoma lines (HNSCC) undergo apoptosis rapidly after treatment with chelerythrine in vitro, we assessed the effects of this agent on p53-deficient SQ-20B HNSCC cells in vivo. The results demonstrate that chelerythrine treatment of nude mice bearing SQ-20B is associated with significant tumor growth delay. Significantly, treatment with chelerythrine resulted in minimal toxicity. These findings demonstrate a potential for chelerythrine as an antitumor drug against squamous cell carcinoma.
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PMID:In vitro and in vivo activity of protein kinase C inhibitor chelerythrine chloride induces tumor cell toxicity and growth delay in vivo. 1069 May 61

Angiogenesis is crucial for many biological and pathological processes including the ovarian cycle and tumor growth. To identify molecules relevant for angiogenesis, we performed mRNA fingerprinting and subsequent Northern blot analysis using bovine cord-forming vs. monolayer-forming endothelial cells (EC) in vitro and staged bovine corpora lutea in vivo. We detected the receptor for activated C kinase 1 (RACK1), the specific receptor for activated protein kinase C beta (PKC beta), to be up-regulated in bovine cord-forming EC in vitro and in angiogenically active stages of bovine corpora lutea in vivo. Thereafter we established and determined the complete bovine RACK1 cDNA sequence. RACK1 was massively induced in subconfluent vs. contact-inhibited bovine EC, during angiogenesis in vitro, active phases of the murine ovarian cycle, human tumor angiogenesis, and in cancer cells in vivo as assessed by quantitative PCR and in situ hybridization. RACK1 transcripts were localized to proliferating EC in vitro and the endothelium of tumor neovascularizations in vivo by in situ hybridization. PKC beta plays an important role in angiogenesis and cancer growth. Our data suggest that downstream signaling of PKC beta in angiogenically active vs. inactive tissues and endothelium is affected by the availability of RACK1.
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PMID:RACK1 is up-regulated in angiogenesis and human carcinomas. 1109 74

Autocrine and paracrine signaling leading to stimulation of tumor cell growth is a common theme in human cancers. In addition to polypeptide growth factors such as EGF family members which signal through receptor tyrosine kinases, accumulating evidence supports the autocrine and paracrine involvement of specific neuropeptides with defined physiologic actions as neurotransmitters and gut hormones in lung, gastric, colorectal, pancreatic and prostatic cancers. These neuropeptides, including gastrin-releasing peptide, neuromedin B, neurotensin, gastrin, cholecystokinin and arginine vasopressin bind seven transmembrane-spanning receptors that couple to heterotrimeric G proteins. Studies with human small cell lung cancer (SCLC) cells support a requirement for balanced signaling through G(q) and G(12/13) proteins leading to intracellular Ca2+ mobilization, PKC activation and regulation of the ERK and JNK MAP kinase pathways. While specific neuropeptide antagonists offer promise for interrupting the single neuropeptide autocrine systems operating in pancreatic and prostatic cancers, SCLC is exemplified by multiple, redundant neuropeptide autocrine systems such that tumor growth cannot be inhibited with a single specific antagonist. However, a novel class of neuropeptide derivatives based on the substance P sequence have been defined that exhibit broad specificity for neuropeptide receptors and induce apoptosis in SCLC by functioning as biased agonists that stimulate discordant signal transduction. Thus, interruption of autocrine and paracrine neuropeptide signaling with specific antagonists or broad-spectrum biased agonists offer promising new therapeutic approaches to the treatment of human cancers.
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PMID:Autocrine and paracrine signaling through neuropeptide receptors in human cancer. 1131 3


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