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)

Survivin is an attractive target for tumor growth inhibition and represents a significant approach to anticancer therapy. RNA interference is an important tool for specifically down-regulating the expression of cellular genes. However, the efficiency of short hairpin RNA (shRNA) on the expression of survivin gene and the influence on the cell apoptosis transfected by the non-viral gene transfer system of ultrasound-targeted microbubble destruction was not explored. In this work, recombinant expression plasmid of shRNA targeting survivin gene was constructed and added to cultured cervical cancer cells followed by ultrasound exposure and SonoVue((R)) microbubble. Expression of survivin mRNA and protein were assessed by RT-PCR and western blot analysis. Apoptosis ratio was quantified by flow cytometry marked with annexin V and 7-AAD. After transfected for 48 h, the expression of survivin mRNA and protein were (16.67 +/- 2.73)% and (21.33 +/- 3.55)%, respectively. The apoptosis rate was (45.41 +/- 1.47)%. The differences were significant as compared with other groups (P < 0.01). In conclusion, we suggested that survivin could be regarded as an ideal anticancer target of cervical cancer. Recombinant expression plasmid of shRNA targeting survivin gene mediated by ultrasound-targeted microbubble destruction technique could effectively inhibit the expression of target gene and induce cell apoptosis. This novel method for RNA interference represents a powerful, promising non-viral technology that can be used in the tumor gene therapy and research.
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PMID:Novel ultrasound-targeted microbubble destruction mediated short hairpin RNA plasmid transfection targeting survivin inhibits gene expression and induces apoptosis of HeLa cells. 1899 Oct 17

The Ras/Raf/MEK pathway represents an important oncogenic signaling pathway in gastrointestinal malignancies, including pancreatic cancer. Although activating B-Raf mutations are infrequent in pancreatic cancer, we hypothesized that targeting Raf could be valuable for therapy of this cancer entity. Moreover, as vascular endothelial growth factor receptor 2 (VEGFR2) is involved in tumor angiogenesis, we sought to investigate the effects of dual inhibition of Raf and VEGFR2 on pancreatic tumor growth, vascularization, and metastasis. Effects of a Raf/VEGFR2 inhibitor (NVP-AAL881) on pancreatic cancer cells, endothelial cells, and vascular smooth muscle cells were determined by Western blotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis, and migration assays, respectively. Changes in the expression of VEGF-A or survivin were investigated by ELISA and/or real-time PCR. The growth-inhibitory effects of Raf/VEGFR2 inhibition were additionally evaluated in orthotopic tumor models. Results showed that various Raf isoforms were activated in pancreatic cancer cells and NVP-AAL881 diminished the activation of MEK, Akt, Erk, and also STAT3. Moreover, dual inhibition of Raf/VEGFR2 significantly reduced VEGF expression and impaired cancer cell migration. Importantly, besides blocking VEGF-induced Erk and SAPK phosphorylation in endothelial cells, the Raf inhibitor diminished STAT3 phosphorylation, independent of a VEGFR2 blockade, and reduced the expression of survivin. In addition, cell proliferation and migration of both endothelial cells and vascular smooth muscle cells were significantly reduced. In vivo, blocking Raf/VEGFR2 significantly inhibited orthotopic tumor growth and vascularization and reduced cancer metastasis. In conclusion, blocking Raf exerts growth-inhibitory effects on pancreatic tumor cells, endothelial cells, and pericytes and elicits antiangiogenic properties. Dual targeting of Raf and VEGFR2 appears to be a valid strategy for therapy of pancreatic cancer.
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PMID:Dual targeting of Raf and VEGF receptor 2 reduces growth and metastasis of pancreatic cancer through direct effects on tumor cells, endothelial cells, and pericytes. 1900 34

Cinobufocini injection is a preparation containing water-soluble components of the toad skin. The aim of the present study was to investigate the apoptosis of human lung adenocarcinoma cell line A 549 induced by cinobufocini. A 549 or HLF-1(human lung fibroblast) cells were treated with cinobufocini at different concentrations for 24 and 48 h, respectively. The proliferation of cells was detected with the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay. Morphology of cells was carried out with scanning electronic microscopy (SEM) and Hoechst 33258 staining. The apoptosis rate was examined by flow cytometry. The expression of survivin was examined with RT-PCR and Western blot assay. The caspase-3 and caspase-7 activities were detected with caspase colorimetric protease assay. We found that cinobufocini significantly inhibited tumor growth of A 549 cells in a dose- and time-dependent manner without damaging non-cancerous cells (HLF-1) and induced granular apoptotic bodies of A 549 cells. Next, cinobufocini increased the percentage of cells in G1 phase and decreased the percentage of cells in S phase in A 549 cells. Furthermore, cinobufocini downregulated the expression of survivin mRNA and protein. Finally, cinobufocini upregulated caspase-3 activity. We concluded that cinobufocini induces apoptosis of A 549 cells, which is associated with the decreasing expression of survivin mRNA and protein, increasing caspase-3 activity of A 549 cells.
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PMID:Involvement of caspase-3 activity and survivin downregulation in cinobufocini-induced apoptosis in A 549 cells. 1924 43

The inhibitor of apoptosis protein survivin is highly expressed in neuroblastoma (NB) and survivin-specific T cells were identified in Stage 4 patients. Therefore, we generated a novel survivin minigene DNA vaccine (pUS-high) encoding exclusively for survivin-derived peptides with superior MHC class I (H2-K(k)) binding affinities and tested its efficacy to suppress tumor growth and metastases in a syngeneic NB mouse model. Vaccination was performed by oral gavage of attenuated Salmonella typhimurium SL7207 carrying pUS-high. Mice receiving the pUS-high in the prophylactic setting presented a 48-52% reduction in s.c. tumor volume, weight and liver metastasis level in contrast to empty vector controls. This response was as effective as a survivin full-length vaccine and was associated with an increased target cell lysis, increased presence of CD8(+) T-cells at the primary tumor site and enhanced production of proinflammatory cytokines by systemic CD8(+) T cells. Furthermore, depletion of CD8(+) but not CD4(+) T-cells completely abrogated the pUS-high mediated primary tumor growth suppression, demonstrating a CD8(+) T-cell mediated effect. Therapeutic vaccination with pUS-high led to complete NB eradication in over 50% of immunized mice and surviving mice showed an over 80% reduction in primary tumor growth upon rechallenge in contrast to controls. In summary, survivin-based DNA vaccination is effective against NB and the rational minigene design provides a promising approach to circumvent potentially hazardous effects of using full length antiapoptotic genes as DNA vaccines.
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PMID:Survivin minigene DNA vaccination is effective against neuroblastoma. 1929 96

Interleukin (IL)-24 is an excellent therapeutic gene for cancer therapy. In this work, IL-24 was inserted into Ad.sp-E1A(Delta24), an oncolytic adenovirus with a 24-bp deletion in the E1A gene, which was driven by the survivin promoter to form Ad.sp-E1A(Delta24)-IL-24. Ad.sp-E1A(Delta24)-IL-24 has an excellent antitumor effect in vitro for human nasopharyngeal, liver, lung, and cervical carcinoma cell lines but does no or little damage to normal cell lines L-02 and WI38. Furthermore, it achieved nearly complete inhibition (although not elimination) of NCI-H460 lung carcinoma growth in nude mice. The antitumor efficacy of Ad.sp-E1A(Delta24)-IL-24 on NCI-H460 cells was clearly mediated by apoptosis, because it induced caspase-3 and poly(ADP-ribose) polymerase cleavage. This is the first report of Ad.sp-E1A(Delta24)-IL-24 with such an excellent, broad, and specific antitumor effect in vitro and nearly complete inhibition of lung tumor growth in vivo.
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PMID:Potent antitumor effect of interleukin-24 gene in the survivin promoter and retinoblastoma double-regulated oncolytic adenovirus. 1932 May 63

Stat3, a member of the signal transducer and activator of transcription family, has the potential to mediate cell survival, growth and differentiation. Stat3 is constitutively activated in numerous cancers, including >50% of breast cancers. Previous studies demonstrated that constitutively activated Stat3 plays an important role in breast cancer development and progression by promoting cell proliferation and inhibiting apoptosis. The present study was designed to investigate the potential use of RNA interference (RNAi) to block Stat3 expression and activation, as well as the subsequent effect on human breast cancer cell growth. Our studies show that knockdown of STAT3 expression by siRNA reduced expression of Bcl-xL and survivin in MDA-MB-231 cells, and also led to Fas mediated intrinsic apoptotic pathway by activating caspases -8, -9, -3 and PARP1 cleavage. In nude mice, pRNAi-Stat3 significantly suppressed tumor growth compared with controls. It also suppressed Stat3 expression, and downregulated BcL-xL and upregulated Fas, Fas-L and cleaved caspase-3 expression within the tumor, which significantly induced apoptosis and led to tumor suppression. Thus, targeting Stat3 signaling using siRNA may serve as a novel therapeutic strategy for the treatment of breast cancers expressing constitutively activated Stat3.
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PMID:Stat3-siRNA induces Fas-mediated apoptosis in vitro and in vivo in breast cancer. 1936 Mar 34

In recent years, Akt signaling has gained recognition for its functional role in more aggressive, therapy-resistant malignancies. As it is frequently constitutively active in cancer cells, several drugs are being investigated for their ability to inhibit Akt signaling. The purpose of this study is to determine effect of diosgenin (fenugreek), a dietary compound on Akt signaling and its downstream targets on estrogen receptor positive (ER(+)) and estrogen receptor negative (ER(-)) breast cancer (BCa) cells. Diosgenin inhibits pAkt expression and Akt kinase activity without affecting PI3 kinase levels, resulting in the inhibition of its downstream targets, NF-kappaB, Bcl-2, survivin and XIAP. The Raf/MEK/ERK pathway, another functional downstream target of Akt, was inhibited by diosgenin in ER(+) but not in ER(-) BCa cells. Additionally, we found that diosgenin caused G1 cell cycle arrest by downregulating cyclin D1, cdk-2 and cdk-4 expression in both ER(+) and ER(-) BCa cells resulting in the inhibition of cell proliferation and induction of apoptosis. Interestingly, no significant toxicity was seen in the normal breast epithelial cells (MCF-10A) following treatment with diosgenin. Additionally, in vivo tumor studies indicate diosgenin significantly inhibits tumor growth in both MCF-7 and MDA-231 xenografts in nude mice. Thus, these results suggest that diosgenin might prove to be a potential chemotherapeutic agent for the treatment of BCa.
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PMID:Diosgenin targets Akt-mediated prosurvival signaling in human breast cancer cells. 1938 50

The non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 muM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.
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PMID:Tolfenamic acid inhibits esophageal cancer through repression of specificity proteins and c-Met. 1940 33

Ovarian cancer has the highest mortality rate among gynecologic malignancies in the world, and the development of drug resistance is a major impediment toward successful treatment of the desease. Emodin has been reported to sensitize human tumor cells to chemotherapeutic agents. The present study investigated whether emodin could overcome chemoresistance of A2780/taxol cells. Cells were treated with different concentration of emodin alone or combined with paclitaxel, then the cell viability was measured by MTT and the apoptosis was determined by flow cytometric analysis. The changes of mRNA and protein were examined by QRT-PCR and Western blotting. The function of P-glycoprotein was also determined by flow cytometry. The results showed that emodin induced apoptosis alone at a high concentration and increased paclitaxel-induced apoptosis at a low concentration. It enhanced the sensitivity of A2780/taxol cells to paclitaxel with down-regulation of P-glycoprotein, XIAP and survivin. Taken together, the results demonstrated a dual role for emodin in the inhibition of drug resistant ovarian tumor growth by increasing paclitaxel cellular concentration and re-sensitizing the resistant cells to paclitaxel. Our results suggest the possibility of an innovative chemotherapeutic strategy that uses emodin in combination with paclitaxel to increase the sensitivity of tumor cells.
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PMID:Emodin sensitizes paclitaxel-resistant human ovarian cancer cells to paclitaxel-induced apoptosis in vitro. 1942 43

Survivin, a member of inhibitor of apoptosis family, is associated with both prostate cancer progression and drug resistance. Therefore, we hypothesized that survivin may play a potentially important role in hormone-refractory prostate cancer (HRPC) and bone metastatic disease; thus, targeting of survivin signaling could enhance therapeutic efficacy in prostate cancer. 3,3'-Diindolylmethane (DIM) has been known to have cancer chemoprevention activity. However, no information is available regarding the down-regulation of survivin by DIM, which could result in the chemosensitization of HRPC cells to Taxotere-induced killing. We investigated the effect of DIM alone or in combination with Taxotere using LNCaP and C4-2B prostate cancer cells. We observed that DIM enhanced Taxotere-induced apoptotic death in both cell lines. These enhancing effects were related to a decrease in survivin expression as well as androgen receptor and nuclear factor-kappaB (NF-kappaB) DNA-binding activity. We also found that knockdown of survivin expression by small interfering RNA transfection increased DIM-induced cell growth inhibition and apoptosis, whereas overexpression of survivin by cDNA transfection abrogated DIM-induced cell growth inhibition and apoptosis in both prostate cancer cells. Importantly, luciferase assays showed a significant reduction of survivin-Luc and NF-kappaB-Luc activity in prostate cancer cells exposed to DIM and Taxotere. Furthermore, combination treatment significantly inhibited C4-2B bone tumor growth, and the results were correlated with the down-regulation of survivin. From these results, we conclude that inactivation of survivin by DIM enhanced the therapeutic efficacy of Taxotere in prostate cancer in general, which could be useful for the treatment of HRPC and metastatic prostate cancer.
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PMID:3,3'-Diindolylmethane enhances taxotere-induced apoptosis in hormone-refractory prostate cancer cells through survivin down-regulation. 1943 6


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