UMLS:C0598934 - FACTA Search

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Query: UMLS:C0598934 (tumor growth)
58,965 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The unselective cyclooxygenase (COX) inhibitor S-flurbiprofen and its-in terms of COX-inhibition-"inactive" enantiomer R-flurbiprofen have been previously found to inhibit tumor development and growth in various animal models. The underlying mechanisms are unknown. Here, we show that both R- and S-flurbiprofen reduce survival of three colon cancer cell lines, which differ in the expression of COX-2 (HCT-15, no COX-2; Caco-2, inducible COX-2; and HT-29, constitutive COX-2). The IC50 for S- and R-flurbiprofen ranged from 250 to 450 microM. Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA- and PARP-cleavage. In addition, R- and S-flurbiprofen caused a G1-cell cycle block. The latter was associated with an activation of c-Jun N-terminal kinase (JNK), an increase of the DNA binding activity of the transcription factor AP-1 and down-regulation of cyclin D1 expression. Western blot analysis, as well as supershift experiments, revealed that the AP-1 activation was associated with a change of AP-1 composition toward an increase of JunB. The JNK inhibitor SP600125 antagonized R- and S-flurbiprofen-induced AP-1 DNA binding, suppression of cyclin D1 expression, and the G1-cell cycle block. However, JNK inhibition had no effect on flurbiprofen-induced apoptosis. Hence, the cell cycle arrest is obviously mediated, at least in part, through JNK-activation, whereas R- and S-flurbiprofen-induced apoptosis is largely independent of JNK. Although in vitro effects of R- and S-flurbiprofen were indistinguishable, only R-flurbiprofen inhibited HCT-15 tumor growth in nude mice, suggesting the involvement of additional in vivo targets, which are differently affected by R- and S-flurbiprofen.
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PMID:Activation of c-Jun-N-terminal-kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers. 1275 38

Silibinin, the flavonoid found in the milk thistle, has been shown to suppress cell growth and exhibit anti-cancer effects. Some flavonoids were reported to inhibit angiogenesis which is essential for tumor growth and metastasis. In this study, to clarify the underlying mechanisms for the anti-cancer effect of silibinin, we examined the effects of silibinin on human endothelial ECV304 cells. Silibinin was found to suppress the growth and induce the apoptosis of ECV304 cells. The induction of apoptosis by silibinin was confirmed by ladder-patterned DNA fragmentation, cleaved and condensed nuclear chromatin and DNA hypoploidy. Silibinin could effectively inhibit constitutive NF-kappaB activation as revealed by electrophoretic mobility shift assay and NF-kappaB-dependent luciferase reporter study. Consistent with this, silibinin treatment resulted in a significant decrease in the nuclear level of p65 subunit of NF-kappaB. In addition, silibinin treatment caused a change in the ratio of Bax/Bcl-2 in a manner that favors apoptosis. Silibinin also induced the cytochrome c release, activation of caspase-3 and caspase-9 and cleavage of PARP. These results suggest that silibinin may exert, at least partly, its anti-cancer effect by inhibiting angiogenesis through induction of endothelial apoptosis via modulation of NF-kappaB, Bcl-2 family and caspases.
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PMID:Involvement of NF-kappaB and caspases in silibinin-induced apoptosis of endothelial cells. 1465 75

Drug resistance is a major impediment to the successful treatment of breast cancer using chemotherapy. The photoactivatable drug calphostin C has shown promise in killing select drug-resistant tumor cells lines in vitro. To assess the effectiveness of this agent in killing doxorubicin- or paclitaxel-resistant breast tumor cells and to explore its mode of action, MCF-7 cells were exposed to increasing concentrations of either doxorubicin or paclitaxel until maximum resistance was obtained. This resulted in the creation of isogenic drug-resistant MCF-7TAX and MCF-7DOX cell lines, which were approximately 50- and 65-fold resistant to paclitaxel and doxorubicin, respectively. Interestingly, calphostin C was able to kill MCF-7TAX cells as efficiently as wildtype MCF-7 cells (IC50s were 9.2 and 13.2 nM, respectively), while MCF-7DOX cells required a 5-fold higher concentration of calphostin C to achieve the same killing (IC50 = 64.2 nM). Consistent with their known mechanisms of action, paclitaxel killed tumor cells by inducing mitotic arrest and cell multinucleation, while doxorubicin induced plasma membrane blebbing and decreased nuclear staining with propidium iodide. In contrast, cytoplasmic vacuolization accompanied cell killing by calphostin C in these cell lines, without the induction of caspase-8 or PARP cleavage or the release of cytochrome c from mitochondria. Calphostin C had little effect on the uptake of either paclitaxel or doxorubicin by the cells. Taken together, the above data suggests that calphostin C is able to potently kill drug-resistant breast tumor cells through a mechanism that may involve the induction of cytoplasmic vacuolization, without activation of typical apoptotic pathways. Consequently, calphostin C may prove useful clinically to combat tumor growth in breast cancer patients whose tumors have become unresponsive to anthracyclines or taxanes, particularly in association with photodynamic therapy.
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PMID:Potent killing of paclitaxel- and doxorubicin-resistant breast cancer cells by calphostin C accompanied by cytoplasmic vacuolization. 1469 56

To increase the chemo-sensitivity of anaplastic thyroid carcinoma, we examined the effects of glycerol on the tumor growth after CDDP treatment. The cultured cells of an anaplastic thyroid carcinoma cell line (8305c) carrying a mutated p53 gene (mp53) were transplanted into the thighs of nude mice. Tumor growth was evaluated until 24 days after intraperitoneal injection of CDDP and/or pre-injection of glycerol to the tumor. We treated the mice with half the tumor volume of glycerol (1.2 M) and/or CDDP at 6 mg/kg (BW) either of which hardly inhibited tumor growth by itself. When we treated the mice with the combination of glycerol and CDDP at these concentrations, however, a clear delay of the tumor growth was observed. We also immunohistochemically analyzed the effects of glycerol on the induction of caspase-3 activity and apoptosis. Cells positive for cleavage to active caspase-3 and 85 kDa PARP, and apoptosis were hardly observed in the tumors when they were treated with glycerol or CDDP alone. In contrast, when they were treated with CDDP combined with glycerol, such positive cells were significantly increased. It has been shown that glycerol synergistically enhanced the effects of CDDP as a tumor suppressive agent through the induction of caspase-3-mediated apoptosis in 8305c tumors. Therefore, glycerol might be useful for chemotherapy in patients with mp53 cancer cells.
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PMID:Glycerol enhances CDDP-induced growth inhibition of thyroid anaplastic carcinoma tumor carrying mutated p53 gene. 1501 Aug 79

Hypoxia inducible factor-1 (HIF-1) is the main transcriptional factor activated by hypoxia. Besides the well-described role assigned to HIF-1 in the adaptation of cells to hypoxia, different recent data describe a possible role for HIF-1 in the modulation of apoptosis. However, this precise role is not yet clearly understood. In this study, chemical and physiological hypoxia, which were shown to induce HIF-1alpha stabilization and HIF-1 activation, were shown to inhibit apoptosis induced in HepG2 cells by two different pro-apoptotic conditions, serum deprivation- and t-BHP-induced oxidative stress. Indeed, hypoxia reduced DNA fragmentation, caspase activation, and PARP cleavage induced by these two pro-apoptotic conditions. These results are very interesting because it is a clear demonstration that hypoxia and chemical hypoxia have a direct protective effect on apoptotic cell death induced by two different stimuli. This observation is an important data in understanding how tumor growth can occur in challenging environmental conditions.
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PMID:Hypoxia and CoCl2 protect HepG2 cells against serum deprivation- and t-BHP-induced apoptosis: a possible anti-apoptotic role for HIF-1. 1509 34

Taurolidine (TRD) was designed in the 1970s as a broad-spectrum antibiotic and is used clinically at high doses without systemic toxicity. We have found that this agent possesses cytotoxic activity in human tumor cell lines and antineoplastic activity in mice bearing i.p. human tumor xenografts. We now report the mechanism by which TRD induces cell death in DU145 human prostate tumor cells. The IC50 (3 days) of TRD in this model was 16.8+/-1.1 microM. Cytotoxicity was associated with DNA debris and increased membrane phosphatidylserine externalization, both suggesting the induction of apoptosis. This was confirmed by the ability of TRD to induce PARP cleavage in these cells, an effect prevented by coexposure to the pan-caspase inhibitor zVAD-FMK. TRD exposure also resulted in the appearance of cytochrome c in the cytoplasm, procaspase 9 activation within 2 h of drug exposure and procaspase 8 activation 4 h after exposure. Parallel experiments revealed that cytochrome c appearance in the cytoplasm was not blocked by preexposure to zVAD-FMK, while activation of both procaspase 9 and procaspase 8 was prevented. Finally, antineoplastic activity was assessed in mice bearing subcutaneous xenografts of DU145 cells. Initial studies quantitated the toxicity of three i.p. injections of TRD, administered as one injection on three alternate days per week, at doses ranging from 500 to 700 mg/kg per injection. The 500 mg/kg dose produced about 7% mortality after three cycles and effectively inhibited tumor growth. Thus, TRD induced mitochondrial-mediated apoptosis in DU145 human prostate tumor cells and this effect could be exploited for therapeutic advantage.
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PMID:Mechanistic and antineoplastic evaluation of taurolidine in the DU145 model of human prostate cancer. 1517 56

The TSLC1 tumor-suppressor gene is silenced in a number of human cancer tissues and cell lines, including lung, prostate, liver, stomach, pancreatic, and breast cancers. Expression of TSLC1 in a non-small-cell lung cancer (NSCLC) cell line A549 suppresses tumorigenicity in nude mice. However, the molecular mechanism of TSLC1 action is not yet elucidated. In the present study, we show that the expression of TSLC1 from a recombinant adenovirus vector (Ad-TSLC1) inhibited cell proliferation and induced apoptosis in the NSCLC cell line A549. We also demonstrated that subcutaneous tumor growth in nude mice induced by A549 cells was suppressed to the extent of 70-80% by intratumoral injection of Ad-TSLC1. Re-expression of TSLC1 also resulted in activation of the apoptotic protease caspase-3, accompanied by the cleavage of its substrate poly (ADP-ribose) polymerase (PARP). The antiproliferative and pro-apoptotic activity of TSLC1 required the presence of the FERM-binding and PDZ-interacting motifs located in the cytoplasmic domain. Our results demonstrate the pro-apoptotic and oncosuppressive activity of TSLC1 protein, and suggest the potential of TSLC1 for gene therapy.
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PMID:Re-expression of TSLC1 in a non-small-cell lung cancer cell line induces apoptosis and inhibits tumor growth. 1518 78

The von Hippel-Lindau (VHL) is a known tumor suppressor that binds to alpha-subunits of hypoxia-inducible factors and induces ubiquitin-mediated degradation of the protein in an oxygen-dependent manner. VHL is also involved in the regulation of tumor angiogenesis, glycolysis, cell cycle regulation, and apoptosis. In the present study, we showed that ectopic expression of VHL induces apoptosis in renal cell carcinoma 786-O cells which contain only the mutant VHL, evidenced by TUNEL assay and DAPI staining. Furthermore, biochemical studies indicated that expression of VHL in 786-O cells results in both PARP and CPP32 cleavage, suggesting that VHL-induced apoptosis in 786-O cells is caspase dependent. Moreover, we also observed that apoptosis induced by ectopic VHL expression was associated with up-regulation of p27 as well as Bax, implicating the roles of these two proteins in VHL-induced apoptosis. The up-regulation of p27 and Bax by VHL was specific since we did not detect any changes in the level of other apoptotic factors including Fas and Bcl2 by the expression of VHL. We next examined the effect of VHL expression on the tumor growth of 786-O renal cell carcinoma cells in nude mouse. The results showed that injection of Ad.VHL adenovirus regresses the tumor growth of 786-O cells in nude mouse. The analysis by TUNEL assay as well as DAPI staining of 786-O tumors injected with Ad.VHL showed clear evidence of apoptosis. These results suggest that ectopic VHL expression induces apoptotic response in 786-O VHL mutant cells both in vitro and in vivo.
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PMID:Ectopic expression of von Hippel-Lindau tumor suppressor induces apoptosis in 786-O renal cell carcinoma cells and regresses tumor growth of 786-O cells in nude mouse. 1524 Jan 40

Increased expression of proinflammatory and proangiogenic factors are associated with aggressive tumor growth and decreased survival of patients with head and neck squamous cell carcinoma (HNSCC). In as much as genes that are regulated by nuclear factor NF-kappaB suppress apoptosis, induce proliferation, and mediate inflammation, angiogenesis and tumor metastasis, agents that suppress NF-kappaB activation have potential as treatment for various cancers including HNSCC. We demonstrate that all HNSCC cell lines expressed constitutively active NF-kappaB and IkappaBalpha kinase (IKK), which is needed for NF-kappaB activation. Treatment of MDA 686LN cells with curcumin (diferuloylmethane), a pharmacologically safe chemopreventive agent, inhibited NF-kappaB activation through abrogation of IKK. As a result expression of various cell survival and cell proliferative genes including Bcl-2, cyclin D1, IL-6, COX-2 and MMP-9 was suppressed. This, in turn, inhibits proliferation of all HNSCC cell lines, arrests cell cycle in G1/S phase (MDA 686LN) and induces apoptosis as indicated by upstream and downstream caspase activation, PARP cleavage, annexin V staining in MDA 686LN cells. Suppression of NF-kappaB by cell-permeable p65-based peptide and NBD peptide also inhibited the proliferation and induced apoptosis in these cells. Our results indicate that curcumin is a potent inhibitor of cell proliferation and an inducer of apoptosis in HNSCC through suppression of IKK-mediated NF-kappaB activation and of NF-kappaB-regulated gene expression.
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PMID:Inhibition of growth and survival of human head and neck squamous cell carcinoma cells by curcumin via modulation of nuclear factor-kappaB signaling. 1525 36

Neuroblastoma is a pediatric tumor accounting for 15% of childhood cancer deaths and has a poor prognosis in children >1 year of age. We investigated the ability of apigenin, a nonmutagenic dietary flavonoid that has been shown to have antitumor effects in various tumor cell lines, to inhibit growth and induce apoptosis of the human neuroblastoma cell lines NUB-7, LAN-5, and SK-N-BE(2). Apigenin inhibited colony-forming ability and survival, and induced apoptosis of NUB-7 and LAN-5 cells. The presence of the C2-C3 double bond and the 4'-OH group on the flavonoid structure correlated with the growth-inhibitory potential of apigenin. Furthermore, apigenin inhibited NUB-7 xenograft tumor growth in anonobese diabetic/severe combined immunodeficiency mouse model, likely by inducing apoptosis. Apigenin did not inhibit survival of primary sympathetic neurons, suggesting that it is not toxic to nontransformed cells. The mechanism of action of apigenin seems to involve p53, as it increased the levels of p53 and the p53-induced gene products p21WAF1/CIP1 and Bax. Furthermore, apigenin (15-60 micromol/L) induced cell death and apoptosis of neuroblastoma cells expressing wild-type but not mutant p53. Apigenin increased caspase-3 activity and PARP cleavage, and Z-VAD-FMK, a broad-spectrum caspase-3 inhibitor, rescued NUB-7 cells from apigenin-mediated apoptosis indicating that apigenin induced apoptosis in acaspase-dependent manner. Overexpression of Bcl-X(L) rescued NUB-7 from apigenin-induced cell death, suggesting that Bax activity is important for the action of apigenin. Apigenin is thus a candidate therapeutic for neuroblastoma that likely acts by regulating a p53-Bax-caspase-3 apoptotic pathway.
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PMID:Induction of caspase-dependent, p53-mediated apoptosis by apigenin in human neuroblastoma. 1565 48

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