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)

Photochemical internalization (PCI) technology has been used for PEI-mediated p53 gene transfer in mice bearing head and neck squamous cell carcinoma (HNSCC) xenografts. Using luciferase as a reporter gene, PCI led to a 20-fold increase in transgene expression 48 h after transfection and sustained transgene expression for 7 days. Therefore, iterative p53 gene transfer was performed by means of a weekly single injection of PEIGlu4/p53 complexes alone or with PCI for 5 (group A) or 7 (group B) weeks. The efficiency of p53 gene therapy was evaluated by following tumor growth and expression of P53-related downstream proteins (P21, MDM2, Bcl2, Bax). Apoptosis induction was evidenced through caspase-3 activation and PARP cleavage. Using PCI, tumor growth inhibition was observed in all transfected animals. Further, successful tumor cure was achieved in 17% (group A) and 83% (group B) of animals. PCI-mediated p53 gene transfer led to higher P53 protein expression that was correlated with induction of Bax and P21 proapoptotic proteins, repression of Bcl2 as well as activation of caspase-3, and cleavage of PARP. The present study demonstrates that PCI enhances the in vivo efficiency of PEI-mediated p53 gene transfer and can be proposed for p53 gene therapy in HNSCC.
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PMID:Eradication of p53-mutated head and neck squamous cell carcinoma xenografts using nonviral p53 gene therapy and photochemical internalization. 1656 29

The effect and mechanism of the ciglitazone on lung cancer cells A549 growth in vitro and in vivo were studied. Various concentrations of ciglitazone were added to the cultured A549 line, and the proliferation and differentiation of A549 cells were examined by MTT and cytometry analysis. A549 cells (1 x 10(6)/mouse) were inoculated subcutaneously into 20 nude mice, which were randomly divided into two groups: the control group, the ciglitazone treated group. The weights of subcutaneous tumors were measured. The expression of cyclin D1 and P21 in the lung was detected by immohistochemistry and Western blot respectively. The results showed that the proliferation of A549 was inhibited significantly by ciglitazone in a dose- and time-dependent manner. There were more cells arrested in G1 /G0 phase and the expression of PPARgamma was markedly up-regulated in ciglitazone-treated group. Direct injection of ciglitazone into A549-induced tumors could suppress tumor growth in nude mice and the growth inhibitory rate was 36%. The expression of cyclin D1 was decreased and P21 increased significantly in ciglitazone-treated group as compared with control group. It was concluded that ciglitazone could inhibit A549 proliferation dose-dependently and time-dependently and induce differentiation, which might be related to the modulation of cell cycle interfered by PPARgamma.
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PMID:Influence of ciglitazone on A549 cells growth in vitro and in vivo and mechanism. 1671 Oct 3

Our previous work has shown that the cancer chemopreventive effect of selenium may in part be mediated by its antiangiogenic activities and that methylseleninic acid (MSeA) can induce G1 arrest of human umbilical vein endothelial (macrovascular) cells. The objectives of the current study are to verify MSeA-induced G1 arrest effect in microvascular endothelial cells and to elucidate the molecular mediators and targets involved. Flow cytometric analysis after MSeA exposure (2-10 microM) of telomerase-immortalized microvascular endothelial (TIME) cells for 24 hr showed aconcentration-dependent increase of G1-arrested cells. MSeA (3 microM) treatment delayed the mitogen-stimulated progression of TIME cells from G1 to S phase. These effects of MSeA were accompanied by an early transient (6 hr) upregulation of P21/CIP1 and P27/KIP1 and a delayed modest increase of P16/INK4a (12 hr). MSeA increased P27/KIP1 mRNA transcript level and slowed the turnover of P21/CIP1 protein. MSeA-treated cells contained elevated levels of bound P16/INK4a within the CDK4/6/cyclin D1 complexes as well as bound P21/CIP1 and P27/KIP1 within the CDK2/cyclin E complex and decreased their kinase activities. MSeA suppressed the mitogen/CDK-driven phosphorylative inactivation of retinoblastoma (Rb) protein, diminishing E2F1 release from Rb. In vivo, daily oral MSeA treatment of nude mice bearing subcutaneously inoculated human prostate cancer DU145 xenografts inhibited tumor growth in a dose-dependent manner. The microvessel density of the tumors in the high MSeA group was decreased by more than half from the control. An inhibition of mitogen-stimulated proliferation of endothelial cells by MSeA may therefore contribute to the inhibition of tumor angiogenesis.
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PMID:Methylseleninic acid inhibits microvascular endothelial G1 cell cycle progression and decreases tumor microvessel density. 1784 21

To investigate the effect of proteasomes reactivator REG gamma on cell cycle and apoptosis in vitro and in vivo. In vitro, we first constructed recombinant plasmid of PcDNA3.1-REGgamma and then transfected REGgamma into MDA-MB-231 cell line. We confirmed the transfection efficiency by Western blot. Subsequently, we observed cell growth, cycle and colony formation. Specific proliferative molecule proliferating cell nuclear antigen (PCNA) and apoptosis related signal molecule Caspase-3 was assayed by immmunohistochemistry and absorption spectrometry, respectively. In vivo, we successfully established transplantation tumor nude mice model. We determined REGgamma mRNA level in the transplantation tumor tissue. Then, FCM was used to determine cell cycle, apoptosis and CD16. Finally, we employed immunohistochemistry to determine P21 positive expression. However, the cells transfected with REGgamma grew more rapidly compared with non-transfected ones. Increased cells were observed in S+G2+M phase and S phase in the REGgamma transfected group. PCNA expression level in the transfected cells was higher than that in non-transfected ones. In vivo, we observed the similar phenomenon including more rapid tumor growth, higher REGgamma mRNA expression, decreased cells number in G0/G1 phase and G2/M phase, increased cells in S phase and decreased apoptosis in the transfected group. In the study of related molecules, we also found related molecules P21 and CD16 positive expression rate were obviously lower than non-infected ones. In present study, we found oncogenicity of MDA-MB-231 cell transfected with REGgamma was enhanced, which might be realized via REGgamma promoting cell growth, inhibiting cell apoptosis, degrading P21 and suppressing activation of NK, suggesting REGgamma promoting tumor growth is a process involving multiple factor mechanisms.
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PMID:Proteasomes reactivator REG gamma enchances oncogenicity of MDA-MB-231 cell line via promoting cell proliferation and inhibiting apoptosis. 1965 65

Interleukin-24 (IL-24)/melanoma differentiation associated gene-7 (mda-7) as a novel tumor-suppressor gene has potent antitumor activities in a broad spectrum of human cancers through the activation of various signaling pathways. However, the suppressive effect of adenovirus-mediated IL-24 (Ad-IL-24) expression on human laryngeal cancers is still elusive. In this study, we explored the therapeutic effect of Ad-IL-24 on human laryngeal cancers in vitro and in vivo in an athymic nude mouse model, using a Hep-2 human laryngocarcinoma cell line, and a WI-38 human diploid cell line served as a normal cell control. We demonstrated that Ad-IL-24 induced significant growth inhibition and apoptosis, upregulated the expression of P21, P27, and Bax, downregulated Bcl-2 expression, and activated caspase-3 in Hep-2 laryngeal tumor cells, while it exerted no direct effect on the in vitro proliferation of WI-38 normal diploid cells. Moreover, intratumoral injections of Ad-IL-24 in nude mice bearing Hep-2 tumors significantly suppressed the laryngeal xengrafted tumor growth and reduced microvessel density (MVD) and VEGF expression in tumors. This retarded tumor growth in vitro and in vivo elicited by Ad-IL-24 was closely associated with the upregulation of proliferation-related molecules P21 and P27, decrease in the ratio of anti- to proapoptotic molecules Bcl-2/Bax, followed by the activation of caspase-3, leading to apoptosis via intrinsic apoptotic pathways, and the reduced expression of proangiogenic factor VEGF involved in the inhibition of tumor angiogenesis. Thus, our results indicate that the potent, selective killing activity of Ad-IL-24 in laryngeal cancer cells, but not in normal cells, makes this vector a potential candidate for laryngeal cancer gene therapy.
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PMID:The in vitro and in vivo antitumor activity of adenovirus-mediated interleukin-24 expression for laryngocarcinoma. 2018 94

The inhibitor of growth (ING) family proteins have been defined as candidate tumor suppressors. ING4 as a novel member of ING family has potential suppressive effect on different tumors via multiple pathways. However, the role of adenovirus-mediated ING4 (Ad-ING4) gene therapy for human breast carcinoma remains unknown. This study investigates the therapeutic effect of Ad-ING4 on human breast cancers in vitro and in vivo in an athymic nude mouse model, using two human breast carcinoma cell lines MDA-MB-231 (mutant p53) and MCF-7 (wild-type p53) and elucidated its underlying mechanism. It was found that Ad-ING4 treatment could induce in vitro significant growth suppression in both mutant p53 MDA-MB-231 and wild-type p53 MCF-7 breast carcinoma cells despite p53 status. This study further demonstrates that Ad-ING4 gene transfer resulted in G2/M phase arrest and apoptosis, upregulated P21, P27, and Bax, downregulated Bcl-2, IL-8, and Ang-1, promoted cytochrome c release from mitochondria into cytosol, and activated caspase-9, caspase-3, and PARP in mutant p53 MDA-MB-231 breast carcinoma cells. Moreover, intratumoral injections of Ad-ING4 in nude mice bearing mutant p53 MDA-MB-231 breast tumors remarkably inhibited the human breast xenografted tumor growth and reduced CD34 expression of tumor vessels and microvessel density. This retarded MDA-MB-231 breast carcinoma growth in vitro and in vivo elicited by Ad-ING4 closely correlated with the upregulation of cell cycle-related molecules P21 and P27, decrease in the ratio of anti- to proapoptotic molecules Bcl-2/Bax, release of cytochrome c from mitochondria into cytosol followed by caspase-9 and -3 activation leading to apoptosis via intrinsic apoptotic pathway, and the reduced expression of proangiogenic factors IL-8 and Ang-1 involved in the inhibition of tumor angiogenesis. Thus, the results indicate that Ad-ING4 is a potential candidate for breast cancer gene therapy.
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PMID:Tumor-suppressive effect of adenovirus-mediated inhibitor of growth 4 gene transfer in breast carcinoma cells in vitro and in vivo. 2070 19

Glioblastoma Multiforme (GBM), the most common and lethal primary human brain tumor, exhibits multiple molecular aberrations. We report that loss of the transcription factor GATA4, a negative regulator of normal astrocyte proliferation, is a driver in glioma formation and fulfills the hallmarks of a tumor suppressor gene (TSG). Although GATA4 was expressed in normal brain, loss of GATA4 was observed in 94/163 GBM operative samples and was a negative survival prognostic marker. GATA4 loss occurred through promoter hypermethylation or novel somatic mutations. Loss of GATA4 in normal human astrocytes promoted high-grade astrocytoma formation, in cooperation with other relevant genetic alterations such as activated Ras or loss of TP53. Loss of GATA4 with activated Ras in normal astrocytes promoted a progenitor-like phenotype, formation of neurospheres, and the ability to differentiate into astrocytes, neurons, and oligodendrocytes. Re-expression of GATA4 in human GBM cell lines, primary cultures, and brain tumor-initiating cells suppressed tumor growth in vitro and in vivo through direct activation of the cell cycle inhibitor P21(CIP1), independent of TP53. Re-expression of GATA4 also conferred sensitivity of GBM cells to temozolomide, a DNA alkylating agent currently used in GBM therapy. This sensitivity was independent of MGMT (O-6-methylguanine-DNA-methyltransferase), the DNA repair enzyme which is often implicated in temozolomide resistance. Instead, GATA4 reduced expression of APNG (alkylpurine-DNA-N-glycosylase), a DNA repair enzyme which is poorly characterized in GBM-mediated temozolomide resistance. Identification and validation of GATA4 as a TSG and its downstream targets in GBM may yield promising novel therapeutic strategies.
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PMID:A GATA4-regulated tumor suppressor network represses formation of malignant human astrocytomas. 2146 20

The combination of lapatinib and capecitabine is approved in Her2+ metastatic breast cancer. However, the pharmacological mechanisms for this association have not been fully elucidated. In this non-clinical study, we evaluated the efficacy of this association on a panel of six human breast cancer cell lines as a means to identify the molecular determinants of response to this combination. Cell viability was evaluated after concomitant/sequential exposure, and response/resistance determinants for each drug such as dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), thymidine phosphorylase, Bax, Bcl2, P21 levels, and phospho p42/44 and HER1/2 signaling pathway were studied. Lapatinib proved to markedly downregulate TS activity, thus suggesting a subsequent better efficacy of capecitabine. Capecitabine optimized the downregulation of p-AKT and p-P42/44 expression by lapatinib. Consequently, we observed an increase in the Bax/Bcl2 ratio and p21 protein expression in cells exposed to the combination. Overall, our data showed that whatever the schedule and the cell line were, additive to synergistic interaction was achieved in our models. The optimal in vitro combination was finally tested in tumor-bearing mice. Our results fully confirmed that associating both drugs led to a 77% reduction in tumor growth as compared with control animals in BT474-xenografted models. Taken together, this non-clinical study shows that lapatinib and capecitabine modulate each other's molecular determinants of response and that concomitant dosing seems to be the optimal way to combine these drugs. Besides, modulation of TS expression by lapatinib makes its association with capecitabine a promising way to overcome breast cancers resistant in relation with TS overexpression.
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PMID:Positive interaction between lapatinib and capecitabine in human breast cancer models: study of molecular determinants. 2162 1

ING4 as a member of inhibitor of growth (ING) tumor suppressor family has potent inhibitory effects on a variety of tumors. Interleukin-24 (IL-24), a cytokine-tumor suppressor, also shows broad-spectrum and tumor-specific antitumor activities. In this report, we constructed an ING4/IL-24 bicistronic adenovirus (Ad-ING4-IL-24) and assessed its combined effect on in vitro and in vivo A549 human non-small cell lung cancer cells. We demonstrated that ING4 and IL-24 combination treatment by adenovirus-mediated ING4 and IL-24 coexpression induced additive growth suppression and apoptosis as well as an overlapping effect on upregulation of P21, P27, Fas, Bax and cleaved Caspases-8, 9, 3 and downregulation of Bcl-2 in in vitro A549 lung carcinoma cells. Moreover, Ad-ING4-IL-24 treatment additively inhibited in vivo A549 lung carcinoma subcutaneous (s.c.) xenografted tumor growth and reduced CD34 and microvessel density in A549 xenografted tumors in athymic nude mice. The enhanced antitumor activity elicited by Ad-ING4-IL-24 was closely associated with the coordinate activation of extrinsic and intrinsic apoptotic pathways and additive inhibition of tumor angiogenesis. Thus, our results indicate that cancer gene therapy combining two or more tumor suppressors such as ING4 and IL-24 may constitute a novel and effective therapeutic strategy for lung carcinoma and other cancers.
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PMID:Enhanced tumor suppression by an ING4/IL-24 bicistronic adenovirus-mediated gene cotransfer in human non-small cell lung cancer cells. 2166 60

The P21-activated kinases (PAK) are emerging antitumor therapeutic targets. In this paper, we describe the discovery of potent PAK inhibitors guided by structure-based drug design. In addition, the efflux of the pyrrolopyrazole series was effectively reduced by applying multiple medicinal chemistry strategies, leading to a series of PAK inhibitors that are orally active in inhibiting tumor growth in vivo.
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PMID:Discovery of pyrroloaminopyrazoles as novel PAK inhibitors. 2255 6


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