Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zoledronic acid (ZOL) has been shown to reduce osteolysis in bone metastasis. Its efficacy in osteosarcoma has not been convincingly proved in a clinically relevant model for the disease. In vitro, ZOL decreased osteosarcoma cell proliferation, mainly due to an increase in apoptosis in a dose-dependent fashion. There was a decrease in cell migration at >or=10 micromol/L concentrations, but invasion was inhibited at a much lower dose of 0.1 micromol/L. Reverse transcription-PCR showed that ZOL overall caused an increased expression of osteocalcin and decreased expression of alkaline phosphatase, osteopontin, osteonectin, and vascular endothelial growth factor, with no change in expression of osteoprotegerin. ZOL administration s.c. twice weekly at 0.12 mg/kg to SaOS-2 tumor-bearing mice resulted in primary tumor growth inhibition, reduction in lung metastases, and dramatic decrease in osteolysis. Furthermore, in the ZOL cohort, there was a clear reduction in the number of osteoclasts in bone exposed to tumor and a lower tumor vessel density. These data point to the adjuvant potential of ZOL in the management of osteosarcoma not only for its antiosteolytic properties but also for its ability to directly halt tumor cell growth and metastasis via its effects on viability, invasion, differentiation, and angiogenesis.
Mol Cancer Ther 2007 Dec
PMID:Zoledronic acid inhibits osteosarcoma growth in an orthotopic model. 1808 20

Metastatic osteosarcoma (OS) has a very poor prognosis. New treatments are therefore wanted. The conditionally replicative adenovirus Ad5-Delta24RGD has shown promising anti-tumor effects on local cancers, including OS. The purpose of this study was to determine whether intravenous administration of Ad5-Delta24RGD could suppress growth of human OS lung metastases. Mice bearing SaOs-lm7 OS lung metastases were treated with Ad5-Delta24RGD at weeks 1, 2 and 3 or weeks 5, 6 and 7 after tumor cell injection. Virus treatment at weeks 1-3 did not cause a statistically significant effect on lung weight and total body weight. However, the number of macroscopic lung tumor nodules was reduced from a median of >158 in PBS-treated control mice to 58 in Ad5-Delta24RGD-treated mice (p = 0.15). Moreover, mice treated at weeks 5-7 showed a significantly reduced lung weight (decrease of tumor mass, p < 0.05), a significantly increased body weight gain (decrease of disease symptoms, p < 0.005) and a reduced number of macroscopic lung tumor nodules (median 60 versus > 149, p = 0.12) compared to PBS treated control animals. Adenovirus hexon expression was detected in lung tumor nodules at sacrifice three weeks after the last intravenous adenovirus administration, suggesting ongoing viral infection. These findings suggest that systemic administration of Ad5-Delta24RGD might be a promising new treatment strategy for metastatic osteosarcoma.
Mol Cancer 2008 Jan 23
PMID:Intravenous administration of the conditionally replicative adenovirus Ad5-Delta24RGD induces regression of osteosarcoma lung metastases. 1821 25

GMC-5-193 (GMC) is a novel anticancer small-molecule quinazolinone analogue with properties that include antimicrotubule activity and inherent fluorescence. The aim of this study was to produce and optimize a systemically administered liposomal formulation for tumor-targeting delivery of GMC to enhance the anticancer effect of this compound and evaluate its bioefficacy. GMC was encapsulated within a cationic liposome, which was decorated on the surface with an anti-transferrin receptor single-chain antibody fragment (TfRscFv) as the tumor-targeting moiety to form a nanoscale complex (scL/GMC). Confocal imaging of fluorescent GMC uptake in a human melanoma cell line, MDA-MB-435, showed higher cellular uptake of GMC when delivered via the liposome complex compared with free GMC. Delivery of GMC by the tumor-targeting liposome nanoimmunocomplex also resulted in a 3- to 4-fold decrease in IC(50) values in human cancer cells [DU145 (prostate) and MDA-MB-435] compared with the effects of GMC administered as free GMC. In addition, the GMC nanoimmunocomplex increased the sensitivity of cancer cells to doxorubicin, docetaxel, or mitoxantrone by approximately 3- to 30-fold. In the MDA435/LCC6 athymic nude mice xenograft lung metastases model, GMC was specifically delivered to tumors by the nanoimmunocomplex. These data show that incorporation of small-molecule therapeutic GMC within the tumor-targeting liposome nanocomplex enhances its anticancer effect.
Mol Cancer Ther 2008 Mar
PMID:Tumor-targeting nanodelivery enhances the anticancer activity of a novel quinazolinone analogue. 1834 43

Experimental animal studies as well as clinical trials have shown that interventions targeting the blood coagulation cascade inhibit cancer cell metastasis. These data support the hypothesis that congenital prothrombotic disorders, like factor V Leiden, facilitate metastasis whereas bleeding disorders, like haemophilia impede metastasis. To test this hypothesis, we subjected factor V Leiden and factor VIII deficient mice to a murine model of experimental lung metastasis. In this model, B16F10 murine melanoma cells are injected into the tail vein resulting in multiple lung metastases within 20 days. Both hemi- and homozygous factor VIII deficient mice were protected against lung metastasis compared to wild-type littermate controls. In contrast, homozygous factor V Leiden mice developed more metastases than wild-type littermates, whereas heterozygous carriers showed an intermediate number of pulmonary foci. Overall, these data show that a congenital susceptibility to either bleeding or thrombosis modifies the metastatic capacity of cancer cells in the bloodstream and suggest that procoagulant phenotypes are a risk factor for tumour metastasis.
J Cell Mol Med 2008 Dec
PMID:Experimental melanoma metastasis in lungs of mice with congenital coagulation disorders. 1922 65

Interleukin 12 (IL-12) is effective in treating systemic microscopic malignancies by inducing T helper 1 (T(H)1) response, inhibiting angiogenesis, and triggering secondary cytokine production. Unfortunately, daily systemic administration of an acute dose of IL-12 protein is very costly and severely toxic. Here, a simple, economic, and less toxic approach, intramuscular administration of IL-12 gene, is provided for treating tumors in three tumor models. The results indicate that intramuscular administration of IL-12 encoding plasmid DNA via electroporation is a promising technology for treating systemic residual malignancies (less than 3-5 mm in diameter), as illustrated by the inhibition of tumor growth and lung metastases as well as the extension of survival rate. This approach is not effective in treating tumors larger than 3-5 mm in diameter.
Methods Mol Biol 2008
PMID:Systemic IL-12 gene therapy for treating malignancy via intramuscular electroporation. 1837 Feb 11

The goal of these studies was to investigate the potential anticancer properties of two naturally occurring plant sources and two manufactured synthetic forms of vitamin E, i. e., RRR-alpha-tocopherol (alphaT), RRR-gamma-tocopherol (gammaT), all-rac-alpha-tocopherol (all-rac-alphaT), and all-rac-alpha-tocopheryl acetate (all-rac-alphaTAc) in breast cancer models. Vitamin E compounds were evaluated in vitro for inhibition of colony formation and induction of apoptosis in human MDA-MB-435 and MCF-7 breast cancer cells and murine 66cl-4 mammary cancer cells and in vivo for ability to reduce tumor growth and lung and lymph node metastases using the transplantable syngeneic BALB/c mouse 66cl-4-GFP mammary cancer model. gammaT inhibited colony formation and induced apoptosis in all three cancer cell lines. alphaT and all-rac-alphaT were less effective and all-rac-alphaTAc was ineffective. gammaT-induced apoptosis was correlated with activation of caspases-8 and -9 and down-regulation of protein expression of c-FLIP and survivin. In vivo study 1 analyses showed that all-rac-alphaT and all-rac-alphaTAc significantly inhibited tumor growth and inhibited both visible and microscopic size lung metastases. In vivo study 2 analyses showed that alphaT and gammaT reduced tumor growth, but only gammaT reduced tumor growth significantly in comparison to control. In conclusion, synthetic, but not natural, vitamin E exhibits promising anti-cancer properties in vivo.
Mol Nutr Food Res 2008 Apr
PMID:In vitro and in vivo evaluation of anticancer actions of natural and synthetic vitamin E forms. 1838 78

Src family tyrosine kinases (SFK) play an important role in growth and metastasis of many types of human malignancies. However, their significance in Ewing's sarcoma remains to be elucidated. The purpose of this study was to evaluate the role of Lyn, one member of the SFK, in Ewing's sarcoma growth and metastasis and to determine whether a SFK inhibitor can induce Ewing's tumor regression. Lyn was expressed and activated in TC71, A4573, and SK-ES human Ewing's sarcoma cells. Lyn expression was seen in 13 of 15 patient tumor samples, 6 of which showed Lyn activation. Specific inhibition of Lyn using small interfering RNA significantly decreased primary tumor growth and lytic activity, and also reduced lung metastases in vivo. Down-regulation of Lyn resulted in decreased invasive capacity of tumor cells in vitro. AP23994, a small-molecule SFK inhibitor, decreased Lyn kinase activity and suppressed TC71 cell growth in vitro in a dose-dependent manner. Furthermore, treatment of mice bearing s.c. TC71 tumors with AP23994 or with polyethylenimine/Lyn-small interfering RNA gene therapy resulted in reduced Lyn kinase activity and significant tumor growth suppression. EWS/FLI-1, which is translocation fusion protein associated with Ewing's sarcoma, regulated Lyn gene expression and kinase activity. These data suggest that targeting Lyn may be a new therapeutic approach in treatment of Ewing's sarcoma.
Mol Cancer Ther 2008 Jul
PMID:Targeting Lyn inhibits tumor growth and metastasis in Ewing's sarcoma. 1864 93

Dietary exposure to soy has been associated with reduced breast cancer incidence. Soy isoflavones and protein components, such as protease inhibitors and the lunasin peptide, have been indicated as potential agents reducing carcinogenesis. In this study, the effect of soy-based diets was evaluated in a transgenic mouse model of breast carcinoma, overexpressing the neu oncogene. Neu female mice were fed for 20 wk a soy- and isoflavone-free diet (IFD), 4RF21 laboratory mouse diet, soy-based, thus isoflavone-rich (STD), or AIN-76-based semisynthetic diets with a soy protein isolate (SPI) or an isoflavone-poor soy protein concentrate (IPSP) as protein source. Mice were then sacrificed and tumors removed. Mammary tumor weights were not different in SPI versus IFD and STD fed mice. In contrast, mice fed IPSP showed reduced tumor progression versus IFD and STD groups (p < 0.05). Moreover, IPSP fed mice showed lower bromo-2'-deoxyuridine (BrdU) incorporation into breast tumor cells compared to STD and SPI fed animals (p < 0.02). Lung metastases were detected in 80% of IFD fed mice, in 70% of mice fed STD and SPI, and only in 50% of the IPSP fed animals. These results indicate that a diet containing an isoflavone-poor soy protein concentrate may inhibit breast tumor progression and metastasis development.
Mol Nutr Food Res 2008 Oct
PMID:Reduced mammary tumor progression in a transgenic mouse model fed an isoflavone-poor soy protein concentrate. 1865 5

Cancer cell invasion is one of the crucial events in local spreading, growth, and metastasis of tumors. The present study investigated the antiinvasive and antimetastatic action of gambogic acid (GA) in MDA-MB-435 human breast carcinoma cells. GA caused a concentration-dependent suppression of cell invasion through Matrigel and significantly inhibited lung metastases of the cells transplanted in vivo. The potent effects of GA have been attributed to its ability to reduce the expression of matrix metalloproteinases (MMP) 2 and 9 in vitro and in vivo both at the protein and mRNA levels, which were associated with protein kinase C (PKC) signaling pathway as supported by the diminished antiinvasive effect of GA in the presence of specific activator of the pathway. Collectively, our data demonstrated that GA exhibited antiinvasion properties on highly invasive cancer cells via PKC mediated MMP-2/9 expression inhibition. This indicated that GA can be served as a potential novel therapeutic candidate for the treatment of cancer metastasis.
J Mol Med (Berl) 2008 Dec
PMID:Involvement of matrix metalloproteinase 2 and 9 in gambogic acid induced suppression of MDA-MB-435 human breast carcinoma cell lung metastasis. 1877 17

Osteosarcoma is the most frequent primary bone tumor that develops mainly during youth, the median age of diagnosis being 18 years. Despite improvement in osteosarcoma treatment, survival rate is only 30% after 5 years for patients with pulmonary metastases at diagnosis. This warrants exploration of new therapeutic options. The anti-bone resorption molecule receptor activator of NF-kappaB (RANK) is very promising, as it may block the vicious cycle between bone resorption and tumor proliferation that takes place during tumor development in bone site. The cDNA encoding murine RANK-Fc (mRANK-Fc) was administered by gene transfer using an amphiphilic polymer in a mouse model of osteolytic osteosarcoma. Clinical and bone microarchitecture variables were assessed by radiography and micro-CT analyses. In vitro experiments were designed to determine the mechanism of action of RANK-Fc on tumor cell proliferation (XTT assays), apoptosis (caspase activation), cell cycle distribution (fluorescence-activated cell sorting analysis), or gene expression (reverse transcription-PCR). RANK-Fc was effective in preventing the formation of osteolytic lesions associated with osteosarcoma development and in reducing the tumor incidence, the local tumor growth, and the lung metastases dissemination leading to a 3.9-fold augmentation of mice survival 28 days after implantation. On the contrary, mRANK-Fc did not prevent the development of nonosseous tumor nodules, suggesting that bone environment is necessary for mRANK-Fc therapeutic efficacy. Furthermore, mRANK-Fc has no direct activity on osteosarcoma cells in vitro. mRANK-Fc exerts an indirect inhibitory effect on osteosarcoma progression through inhibition of bone resorption.
Mol Cancer Ther 2008 Oct
PMID:Therapeutic efficacy of soluble receptor activator of nuclear factor-kappa B-Fc delivered by nonviral gene transfer in a mouse model of osteolytic osteosarcoma. 1885 42


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