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)

High atomic number material, such as gold, may be used in conjunction with radiation to provide dose enhancement in tumors. In the current study, we investigated the dose-enhancing effect and apoptotic potential of gold nanoparticles in combination with single-dose clinical electron beams on B16F10 melanoma tumor-bearing mice. We revealed that the accumulation of gold nanoparticles was detected inside B16F10 culture cells after 18 h of incubation, and moreover, the gold nanoparticles were shown to be colocalized with endoplasmic reticulum and Golgi apparatus in cells. Furthermore, gold nanoparticles radiosensitized melanoma cells in the colony formation assay (P = 0.02). Using a B16F10 tumor-bearing mouse model, we further demonstrated that gold nanoparticles in conjunction with ionizing radiation significantly retarded tumor growth and prolonged survival compared to the radiation alone controls (P < 0.05). Importantly, an increase of apoptotic signals was detected inside tumors in the combined treatment group (P < 0.05). Knowing that radiation-induced apoptosis has been considered a determinant of tumor responses to radiation therapy, and the length of tumor regrowth delay correlated with the extent of apoptosis after single-dose radiotherapy, these results may suggest the clinical potential of gold nanoparticles in improving the outcome of melanoma radiotherapy.
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PMID:Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice. 1841 Apr 3

Preexisting and acquired resistance to epidermal growth factor receptor (EGFR) inhibitors limits their clinical usefulness in patients with advanced non-small cell lung cancer (NSCLC). This study characterizes the efficacy and mechanisms of the combination of gefitinib or erlotinib with OSU-03012, a celecoxib-derived antitumor agent, to overcome EGFR inhibitor resistance in three NSCLC cell lines, H1155, H23, and A549. The OSU-03012/EGFR inhibitor combination induced pronounced apoptosis in H1155 and H23 cells, but not in A549 cells, suggesting a correlation between drug sensitivity and basal phospho-Akt levels independently of EGFR expression status. Evidence indicates that this combination facilitates apoptosis through both Akt signaling inhibition and up-regulation of endoplasmic reticulum (ER) stress-induced, GADD153-mediated pathways. For example, ectopic expression of constitutively active Akt significantly attenuated the inhibitory effect on cell survival, and small interfering RNA-mediated knockdown of GADD153 protected cells from undergoing apoptosis in response to drug cotreatments. Furthermore, the OSU-03012/EGFR inhibitor combination induced GADD153-mediated up-regulation of death receptor 5 expression and subsequent activation of the extrinsic apoptosis pathway. It is noteworthy that the ER stress response induced by this combination was atypical in that the cytoprotective pathway was not engaged. In addition, in vivo suppression of tumor growth and modulation of intratumoral biomarkers were observed in a H1155 tumor xenograft model in nude mice. These data suggest that the concomitant modulation of Akt and ER stress pathways with the OSU-03012/EGFR inhibitor combination represents a unique approach to overcoming EGFR inhibitor resistance in NSCLC and perhaps other types of cancer with elevated basal Akt activities.
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PMID:Targeting endoplasmic reticulum stress and Akt with OSU-03012 and gefitinib or erlotinib to overcome resistance to epidermal growth factor receptor inhibitors. 1841 50

Chronic infection with hepatitis C virus (HCV) can induce insulin resistance (IR) in a genotype-dependent fashion, thus contributing to steatosis, progression of fibrosis and resistance to interferon therapy. The molecular mechanisms in genotype 1 patients that lead to metabolic syndrome are still ambiguous. Based on our current understanding, HCV proteins associate with mitochondria and endoplasmic reticulum and promote oxidative stress. The latter mediates signals involving the p38 mitogen-activated protein kinase and activates nuclear factor kappa B. This transcription factor plays a key role in the expression of cytokines, tumor necrosis factor alpha (TNF-alpha), interleukin 6, interleukin 8, tumor growth factor beta, and Fas ligand. TNF-alpha inhibits the function of insulin receptor substrates and decreases the expression of the glucose transporter and lipoprotein lipase in peripheral tissues, which is responsible for the promotion of insulin resistance. Furthermore, reduced adiponectin levels, loss of adiponectin receptors, and decreased anti-inflammatory peroxisome proliferator-activated receptor alpha in the liver of HCV patients may contribute to reduced fatty acid oxidation, inflammation, and eventually lipotoxicity. This chain of events may be initiated by HCV-associated IR and provides a direction for future research in the areas of therapeutic intervention.
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PMID:Hepatitis C virus infection: molecular pathways to metabolic syndrome. 1875 83

Pancreatic endoplasmic reticulum kinase (PERK)-eIF2 alpha signaling, a component of the endoplasmic reticulum (ER) stress response, has been proposed as a therapeutic target due to its importance to cell survival in hypoxic tumors. In this study, we show that in addition to promoting survival, PERK can also suppress tumor growth of advanced carcinomas. Our results show that in squamous carcinoma T-HEp3 cells, which display low PERK-eIF2 alpha signaling, inducible activation of an Fv2E-PERK fusion protein results in a strong G(0)-G(1) arrest in vitro. Most importantly, Fv2E-PERK activation, in addition to promoting survival in vitro, inhibits T-HEp3 and SW620 colon carcinoma growth in vivo. Increased PERK activation is linked to enhanced p-eIF2 alpha levels, translational repression, and a decrease in Ki67, pH 3, and cycD1/D3 levels, but not to changes in angiogenesis or apoptosis. Experimental reduction of PERK activity, or overexpression of GADD34 in a spontaneously arising in vivo quiescent variant of HEp3 cells that displays strong basal PERK-eIF2 alpha activation, reverts their quiescent phenotype. We conclude that the growth-inhibitory function of PERK is preserved in tumors and upon proper reactivation can severely inhibit tumor growth through induction of quiescence. This is an important consideration in the development of PERK-based therapies, as its inhibition may facilitate the proliferation of slow-cycling or dormant tumor cells.
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PMID:Dual function of pancreatic endoplasmic reticulum kinase in tumor cell growth arrest and survival. 1845 Nov 52

mda-7/IL-24 shows tumor-suppressor activity in a broad spectrum of human cancer cells. However, the molecular mechanism by which mda-7/IL-24 induces apoptosis is not well understood and most likely involves different pathways depending on the tumor. We examined the apoptotic effect of the adenovirus-mediated mda-7/IL-24 (Ad.mda-7) on human HepG2 hepatoma cells. We found that blocking the endoplasmic reticulum (ER) stress inhibited apoptosis induced by Ad.mda-7 and down-regulated the expression of caspase-12, Bax and caspase-3. The treatment of subcutaneous tumor xenografts of HepG2 cells with Ad.mda-7 inhibited tumor growth and angiogenesis. As in the in vitro studies, we found that blocking ER stress prevented Ad.mda-7 from inducing apoptosis in liver cancer cells in vivo. Our studies suggest that Ad.mda-7 induces apoptosis of HepG2 cells mainly through activation of the ER stress pathway.
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PMID:mda-7/IL-24 induces apoptosis in human HepG2 hepatoma cells by endoplasmic reticulum stress. 1863 9

Glucose-regulated protein 78 (Grp78) is an endoplasmic reticulum chaperone protein and is overexpressed in various cancers. However, it is unclear how significance of this molecule play an active role contributing to the oncogenic effect of head and neck cancer (HNC). To investigate the potential function of Grp78, six HNC cell lines were used. We found that Grp78 is highly expressed in all six cell lines and many of the proteins were localized in the periphery regions, implying other function of this molecule aside from endoplasmic reticulum stress response. Knockdown of Grp78 by small interfering RNA significantly reduced cell growth and colony formation to 53% to 12% compared with that of controls in all six HNC cell lines. Using in vitro wound healing and Matrigel invasion assays, we found that cell migration and invasive ability were also inhibited to 23% to 2% in all these cell lines tested. In vivo xenograft studies showed that administration of Grp78-small interfering RNA plasmid into HNC xenografts significantly inhibited both tumor growth in situ (>60% inhibition at day 34) and liver metastasis (>90% inhibition at day 20). Our study showed that Grp78 actively regulates multiple malignant phenotypes, including cell growth, migration, and invasion. Because knockdown Grp78 expression succeeds in the reduction of tumor growth and metastatic potential, this molecule may serve as a molecular target of therapeutic intervention for HNC.
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PMID:Glucose-regulated protein 78 regulates multiple malignant phenotypes in head and neck cancer and may serve as a molecular target of therapeutic intervention. 1879 Jul 59

Poorly formed tumor blood vessels lead to regions of microenvironmental stress due to depletion of oxygen and glucose and accumulation of waste products (acidosis). These conditions contribute to tumor progression and correlate with poor patient prognosis. Here we show that the microenvironmental stresses found in the solid tumor are able to inhibit the canonical Wnt/beta-catenin signaling pathway. However, tumor cells harboring common beta-catenin pathway mutations, such as loss of adenomatous polyposis coli, are insensitive to this novel hypoxic effect. The underlying mechanism responsible is hypoxia-induced endoplasmic reticulum (ER) stress that inhibits normal Wnt protein processing and secretion. ER stress causes dissociation between GRP78/BiP and Wnt, an interaction essential for its correct posttranslational processing. Microenvironmental stress can therefore block autocrine and paracrine signaling of the Wnt/beta-catenin pathway and negatively affect tumor growth. This study provides a general paradigm relating oxygen status to ER function and growth factor signaling.
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PMID:Tumor hypoxia blocks Wnt processing and secretion through the induction of endoplasmic reticulum stress. 1882 43

1,1-Bis(3'-indoly)-1-(p-substituted phenyl)methanes (C-DIM) exhibit structure-dependent activation of peroxisome proliferator-activated receptor gamma and nerve growth factor-induced Balpha (Nur77) and induce receptor-dependent and receptor-independent apoptosis in cancer cells and tumors. In this study, we investigated the activation of apoptosis in pancreatic cancer cells by p-bromo (DIM-C-pPhBr) and p-fluoro (DIM-C-pPhF) and structurally related analogues that do not activate either peroxisome proliferator-activated receptor gamma or Nur77. The ortho, meta, and para-bromo and -fluoro isomers all activated endoplasmic reticulum (ER) stress-dependent apoptosis in pancreatic cancer cells; however, methylation of the indole N group significantly decreased activity, suggesting that a free N was important for activation of ER stress. Both DIM-C-pPhBr and DIM-C-pPhF resembled the classic ER stress inducer thapsigargin in pancreatic cancer cells and activated ER stress markers, such as glucose-related protein 78 and the c-Jun NH(2) kinase pathway, resulting in the induction of CCAAT/enhancer-binding protein homologous protein, death receptor 5, and the extrinsic apoptotic pathway. Moreover, DIM-C-pPhBr also inhibited tumor growth in an orthotopic model for pancreatic cancer, demonstrating the clinical potential for this C-DIM compound in pancreatic cancer chemotherapy.
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PMID:Structure-dependent activation of endoplasmic reticulum stress-mediated apoptosis in pancreatic cancer by 1,1-bis(3'-indoly)-1-(p-substituted phenyl)methanes. 1885 39

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity toward tumor cells by inducing production of reactive oxygen species such as singlet oxygen. PDT leads to oxidative damage of cellular macromolecules, including proteins that undergo multiple modifications such as fragmentation, cross-linking, and carbonylation that result in protein unfolding and aggregation. Because the major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in endoplasmic reticulum (ER), aggravated ER stress, and potentiated cytotoxicity toward tumor cells. We observed that Photofrin-mediated PDT leads to robust carbonylation of cellular proteins and induction of unfolded protein response. Pretreatment of tumor cells with three different proteasome inhibitors, including bortezomib, MG132, and PSI, gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells of murine (EMT6 and C-26) as well as human (HeLa) origin to PDT-mediated cytotoxicity. Significant retardation of tumor growth with 60% to 100% complete responses was observed in vivo in two different murine tumor models (EMT6 and C-26) when PDT was combined with either bortezomib or PSI. Altogether, these observations indicate that combination of PDT with proteasome inhibitors leads to potentiated antitumor effects. The results of these studies are of immediate clinical application because bortezomib is a clinically approved drug that undergoes extensive clinical evaluations for the treatment of solid tumors.
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PMID:Proteasome inhibition potentiates antitumor effects of photodynamic therapy in mice through induction of endoplasmic reticulum stress and unfolded protein response. 1943 17

Terpyridineplatinum(II) complexes (TPCs) efficiently inhibit the proliferation of glioblastoma cells in vitro and have been tested successfully in a rodent glioblastoma model. Apart from intercalation with DNA, the major mechanism of action of TPCs is a very potent and specific interaction with the human selenoprotein thioredoxin reductase (TrxR). TrxR plays a crucial role in cellular redox homeostasis and protection against oxidative damage. In many malignant cells the thioredoxin system is upregulated, promoting tumor growth and progression. Thus, the thioredoxin system has been proposed to be an attractive target for cancer therapy. This study gives the first comprehensive overview of the effects of TPCs on the transcriptome and proteome of glioblastoma cells. We reveal that under TPC treatment, mechanisms countersteering TrxR inhibition are activated in parallel to DNA-damage-responsive pathways. TPC pressure results in long-term compensatory upregulation of TrxR expression. In parallel, p53 is activated, leading to a range of regulations typical for cell-cycle-arrested cells such as upregulation of CDKN1A, induction of GADD45, inhibition of eIF5A maturation, and reduced phosphorylation of stathmin. We also show that TPCs induce endoplasmic reticulum stress, as they activate the unfolded protein response. This profiling study provides a thorough insight into the spectrum of cellular events resulting from specific TrxR inhibition and characterizes the TPC mode of action.
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PMID:Differential genomic and proteomic profiling of glioblastoma cells exposed to terpyridineplatinum(II) complexes. 1943 28


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