Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently identified 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the mevalonate pathway, as a potential therapeutic target of the head and neck squamous cell carcinomas (HNSCC) and cervical carcinomas (CC). The products of this complex biochemical pathway, including de novo cholesterol, are vital for a variety of key cellular functions affecting membrane integrity, cell signaling, protein synthesis, and cell cycle progression. Lovastatin, a specific inhibitor of HMG-CoA reductase, induces a pronounced apoptotic response in a specific subset of tumor types, including HNSCC and CC. The mediators of this response are not well established. Identification of differentially expressed genes represents a feasible approach to delineate these mediators as lovastatin has the potential to modulate transcription indirectly by perturbing levels of sterols and other mevalonate metabolites. Expression analysis following treatment of the HNSCC cell lines SCC9 or SCC25 with 10 microM lovastatin for 1 day showed that less than 2% (9 cDNAs) of the 588 cDNAs on this microarray were affected in both cell lines. These included diazepam-binding inhibitor/acyl-CoA-binding protein, the activated transcription factor 4 and rhoA. Because the biosynthesis of mevalonate leads to its incorporation into more than a dozen classes of end products, their role in lovastatin-induced apoptosis was also evaluated. Addition of the metabolites of all the major branches of the mevalonate pathway indicated that only the nonsterol moiety, geranylgeranyl pyrophosphate (GGPP), significantly inhibited the apoptotic effects of lovastatin in HNSCC and CC cells. Because rhoA requires GGPP for its function, this links the microarray and biochemical data and identifies rhoA as a potential mediator of the anticancer properties of lovastatin. Our data suggest that the depletion of nonsterol mevalonate metabolites, particularly GGPP, can be potential mediators of lovastatin-induced apoptosis of HNSCC and CC cells.
Neoplasia
PMID:Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. 1208 50

Lovastatin, a drug successfully used in the clinic to prevent and to treat coronary heart disease, has recently been reported to decrease the incidence of melanoma in lovastatin-treated patients. Lovastatin has also been proved to potentiate antitumor effects of both cisplatin and TNF-alpha in murine melanoma models. Recently, an augmented therapeutic effect of lovastatin and doxorubicin has been reported in 3 tumor models in mice. In our preliminary study lovastatin caused retardation of melanoma growth in mice treated with doxorubicin (Feleszko et al. J Natl Cancer Inst 1998;90:247-8). In the present report, we supplement our preliminary observations and demonstrate in 2 murine and 2 human melanoma cell lines that lovastatin effectively potentiates the cytostatic/cytotoxic activity of doxorubicin in vitro via an augmentation of apoptosis (estimated with PARP-cleavage assay, annexin V assay and TUNEL). The combined antiproliferative activity of lovastatin and doxorubicin was evaluated using the combination index (CI) method of Chou and Talalay, revealing synergistic interactions in melanoma cells exposed to lovastatin and doxorubicin. In B16F10 murine melanoma model in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (5 mg/kg for 14 days) and doxorubicin (4 x 1 mg/kg) as compared with either agent acting alone. Lovastatin treatment resulted also in significant reduction of the number of experimental metastasis in doxorubicin-treated mice. The results of our studies suggest that lovastatin may enhance the effectiveness of chemotherapeutic agents in the treatment of malignant melanomas.
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PMID:Lovastatin potentiates antitumor activity of doxorubicin in murine melanoma via an apoptosis-dependent mechanism. 1211 96

Ras-homologous GTPases are involved in the regulation of genotoxic stress-induced gene expression and cell death. Since they need C-terminal isoprenylation for correct intracellular localization and function, we investigated whether depletion of cells from isopren precursor moieties using the HMG-CoA reductase inhibitor lovastatin affects cellular sensitivity to DNA damaging drugs. Here we show that lovastatin renders cells highly resistant to the tumor-therapeutic compound doxorubicin. Desensitization by lovastatin was reverted by co-treatment with GGPP indicating that inhibition of protein geranylgeranylation is involved in acquired doxorubicin resistance. Lovastatin does not influence cellular sensitivity to DNA damaging compounds such as cisplatin, methyl methanesulfonate and ionizing radiation. The frequency of apoptotic cell death induced by doxorubicin was not affected by lovastatin as shown by both annexin V and DNA fragmentation assay. However, lovastatin releases cells from doxorubicin induced G2 blockage. Furthermore, lovastatin protects cells from doxorubicin-induced DNA strand breakage without affecting drug uptake or the expression of multidrug resistance protein (mdr-1). Since lovastatin confers cross-resistance to the topoisomerase II specific inhibitor etoposide, we suggest desensitization by the statin to be related to topoisomerase II function. The finding that lovastatin renders cells resistant to doxorubicin and etoposide by reducing their genotoxic and cytotoxic effects might have clinical implications for cancer therapy.
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PMID:The HMG-CoA reductase inhibitor lovastatin protects cells from the antineoplastic drugs doxorubicin and etoposide. 1223 96

Lovastatin is a competitive inhibitor of 3-hydroxy 3-methylglutaryl coenzyme A reductase, the key regulatory enzyme of cholesterol biosynthesis. This enzyme catalyzes the formation of mevalonate, which is also the precursor of isoprenoid moieties, such as farnesol and geraniol, that are incorporated into several molecules essential for tumor cell signaling. Here, we describe that pretreatment with a non-cytotoxic concentration of lovastatin (10 microM) dramatically inhibited the metastatic ability of F311 mammary carcinoma cells in syngeneic BALB/c mice. Similarly, daily i.p. treatment of animals with a well-tolerated dose of lovastatin (10 mg/kg/day) significantly reduced the number of experimental lung metastases. In vitro, incubation of F3II monolayers in the presence of lovastatin caused a rounded-cell morphology. Immunofluorescence analysis revealed a lack of cortical actin organization, micrutubule disruption and inhibition of integrin-mediated focal contacts in lovastatin-treated cells. Exposure of F3II cells to lovastatin significantly inhibited tumor cell adhesion and migration, and coincubation with the cholesterol precursor mevalonate prevented these effects. Lovastatin reduced membrane localization of Rho protein, a signaling molecule involved in the regulation of actin-based cell motility that needs geranylation for membrane association and activation. In addition, lovastatin induced a dose-dependent inhibition in the secretion of urokinase, a key proteolytic enzyme during tumor invasion and metastasis, and a significant increase of tissue-type plasminogen activator, a marker of good prognosis in mammary cancer. These data suggest that antimetastatic properties of lovastatin are strongly associated with alterations in cytoskeleton organization and the consequent modulation of adhesion, motility and proteolysis.
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PMID:Lovastatin alters cytoskeleton organization and inhibits experimental metastasis of mammary carcinoma cells. 1240 93

Brain tumor formation and growth is accompanied by the proliferation and infiltration of blood capillaries. The phenotypes of endothelial cells that make up capillaries are known to differ not only in the tissues in which endothelial cells are located but also as a result of the microenvironment to which they are exposed. For this reason, primary cultures of brain endothelial cells were isolated from human brain tumors removed by surgery and compared with cells from normal tissue. The primary confluent monolayers that grew out of isolated capillary fragments consisted of closely associated, elongated, fusiform-shaped cells. But brain tumor-derived endothelial cells in culture exhibited significantly less expression of endothelial-specific Factor VIII-related antigen compared with cells isolated from normal tissue. Cultured cells that exhibited binding of Ulex europaeus lectin were shown to take up Dil-Ac-Ldl and formed continuous monolayers that were joined together by tight junctions. The cells also exhibited characteristics of the cells of the brain microvasculature in vitro as seen by the presence of large numbers of mitochondria and few pinocytotic vesicles and by the absence of Weibel-Palade bodies within the cells. The expression of vascular cell adhesion molecule-1, E-Selectin, and the tight junction associated protein ZO-1 but not intercellular adhesion molecule-1 was demonstrated by immunohistological staining or reverse transcriptase-polymerase chain reaction methodologies. Comparative studies of these endothelial cells with endothelial cells from normal tissue will be useful for determining and understanding how the blood-brain barrier differs and functions in tumor and healthy tissues and may lead to strategies for brain tumor therapeutic approaches.
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PMID:Isolation and molecular characterization of brain microvascular endothelial cells from human brain tumors. 1241 24

The effects of lovastatin, a potent inhibitor of HMG CoA reductase, on experimental mammary and prostate oncogenesis, were studied in vitro and in vivo. Lovastatin inhibited cell growth in vitro in a dose-dependent manner for both mammary and prostate cancer cell lines, which was associated with p53-independent apoptosis. Flow cytometric analyses of lovastatin-treated mammary and prostate cancer cells demonstrated cell-cycle G(1) arrest, as well as decreases in S and G(2)/M fractions. p21(Waf1) and p27(Kip1) were induced by lovastatin in both types of cancer cells. Gene expression profiling of cells treated with lovastatin, however, was remarkable for a paucity of transcriptional changes induced by lovastatin. Treatment with lovastatin for 4 weeks did inhibit the formation of pre-neoplastic mammary intraepithelial neoplasias (MIN) in vivo, but not invasive carcinomas in the C3(1)/SV40 TAg transgenic model of mammary cancer. The decreased multiplicity of MIN lesions was associated with increased levels of apoptosis in these lesions. However, cell proliferation in the mammary lesions was not significantly different between lovastatin-treated and control mice 1 day after lovastatin treatment. In female mice treated with lovastatin for 12 weeks, there was a tendency for reduced tumor volume, which did not reach statistical significance. However, lovastatin did not suppress any lesion formation in the prostate of C3(1)/SV40 TAg transgenic male mice. Our results suggest that as lovastatin exerts an inhibitory effect on the development of early mammary lesions of mammary carcinogenesis, this compound may be useful for the chemoprevention of mammary cancer and might have utility as an adjuvant in breast cancer therapy. The chemopreventive effects of lovastatin in vivo, however, may be tissue-specific.
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PMID:Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models. 1266 4

Antiangiogenic therapy is a promising new strategy to inhibit tumor growth and formation of metastases. VEGF (vascular endothelial growth factor) is known to be the most important proangiogenic factor, necessary for the development of new tumor vessels. Specific inhibitors of the VEGF receptor tyrosine kinases, like PTK787/ZK222584 (PTK/ZK), have shown antitumoral and antiangiogenic activity in several animal models. Ongoing early clinical trials with antiangiogenic compounds reveal the need for diagnostic methods to detect their biological activity. Pro-angiogenic growth factors like VEGF and bFGF (basic fibroblast growth factor), soluble variants of proangiogenic receptors like sFLT-1 and sTIE-2, as well as endothelial activation markers like sE-Selectin, can be measured in the serum and plasma of patients by the ELISA technique. They were detected in various malignant diseases to assess their use as surrogate markers in tumor angiogenesis. In different clinical Phase I trials with antiangiogenic compounds, these soluble markers were used to detect dose levels for biological activity. Soluble markers of tumor angiogenesis can be used as prognostic markers in various malignancies like colon cancer or multiple myeloma. Furthermore, they correlated with disease activity, prognosis and imaging techniques for the detection of vascular changes. In clinical Phase I trials with specific inhibitors of the VEGF receptor tyrosine kinases, VEGF serum levels increased in patients treated with higher doses, indicating increasing tumor hypoxia. Taking results from imaging techniques such as dynamic enhanced MRI into account, optimal doses for biological activity could be concluded. New biological treatment techniques will need new diagnostic methods to assess their specific biological activity in patients. Soluble markers and imaging techniques are useful tools for the detection of hypoxia under antiangiogenic treatment. Nevertheless, these techniques are still experimental. Therefore, further clinical evaluation is necessary.
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PMID:Soluble markers for the detection of hypoxia under antiangiogenic treatment. 1282 Mar 65

The level of TNFalpha expression is increased after partial hepatectomy, and experimental evidence exists that TNFalpha plays a key role in liver regeneration. Contradictory results are reported about the influence of TNFalpha on tumor growth: on the one hand, stimulation of tumor growth in various animal models and, on the other hand, intraperitoneally administered TNFalpha leads to reduced metastasis formation. TNFalpha may be one responsible factor for increased metastasis formation after surgical trauma. The objective of our study was to clarify the influence of TNFalpha on the formation of liver metastases in a syngenic mouse model in vivo. We used a novel marker system, EGFP transfected C26 tumor cells for in vivo observation of metastasis formation by intravital microscopy. We analyzed the effect of intraperitoneal TNFalpha-injection on tumor cell adhesion, extravasation and tumor development. The expression of ICAM-1, VCAM-1 and E-Selectin was measured by Western blot and immunohistochemical staining. Tumor load was assessed by determining EGFP in Western blots. GdCl(3) was employed 24 and 48 hr before tumor cell injection to selectively deplete the liver of functioning Kupffer cells. We observed significantly more extravasated tumor cells in the TNFalpha-pre-treated animals at early time points with increased expression of adhesion molecules. Measurement of the EGFP levels showed fewer liver metastases in the TNFalpha-pretreated animals at day 8. After GdCl(3) pretreatment even lower levels of EGFP, i.e., fewer metastases and also lower expression levels of ICAM-1, VCAM-1 and E-Selectin could be observed. TNFalpha, acts in a bidirectional manner: whereas TNFalpha facilitates tumor cell adhesion and extravasation of C26 tumor cells by inducing the expression of adhesion molecules, at later time points, TNFalpha seems to hinder the formation of liver metastases.
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PMID:Influence of TNFA on the formation of liver metastases in a syngenic mouse model. 1292 51

E-selectin mediated cell-cell adhesion plays an important role in inflammatory processes and extravasation of tumor cells. Tumor necrosis factor-alpha (TNF-alpha) induces E-selectin gene and protein expression in primary human endothelial cells (HUVEC) and in an endothelial cell line (EA.hy-926). As shown by ELISA and FACS analyses, HMG-CoA reductase inhibitors (e.g., lovastatin) impair the TNF-alpha stimulated increase in E-selectin protein expression. Similar results were obtained for E-selectin mRNA expression and promoter activity, indicating that the effect of lovastatin is based on inhibition of gene expression. The effective inhibitory concentration of lovastatin was in a physiologically relevant range (IC50<0.1 microM). Lovastatin-mediated block of TNF-alpha induced E-selectin expression is due to inhibition of protein geranylgeranylation rather than farnesylation. Down-regulation of Rho signaling by coexpression of dominant-negative Rho mutants (i.e RhoA, RhoB and Rac) impaired TNF-alpha driven E-selectin gene expression, indicating Rho signaling to be essential for transcriptional activation of the E-selectin gene. Inhibition of E-selectin expression by lovastatin gives rise to a significant reduction in TNF-alpha stimulated adhesion of colon carcinoma cells to HUVEC. Furthermore, low concentration of lovastatin (i.e., < or =1 microM) attenuated TNF-alpha induced tumor cell invasion in vitro. The data support the view that statins might be clinically useful in protection against E-selectin mediated metastasis.
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PMID:Lovastatin inhibits Rho-regulated expression of E-selectin by TNFalpha and attenuates tumor cell adhesion. 1463 Jul 1

Statins have been used successfully in the treatment of hypercholesterinaemia. Moreover, in vitro studies have shown that statins can trigger apoptosis in a variety of tumor cell lines. In the present study we analysed the effect of mevastatin--a novel inhibitor of HMG-COA reductase, the rate-limiting enzyme of the mevalonate pathway--on U266 human myeloma cells. Apoptosis induced by mevastatin was associated with increased caspase activity and depolarisation of the mitochondrial membrane. Expression of Bcl-2 mRNA and protein was down-regulated, with no change in Bax or Bcl-XL protein production. The mitochondrial program was supported by caspase-8 and cleaved-Bid activity. None of the antibodies neutralizing the death-ligand/death-receptor pathway--TRAIL-R2Fc, anti-TNF-alpha, anti-FASL(NOK-1)--influenced the mevastatin-induced apoptosis. Mevastatin also stimulated shedding of syndecan-1 from the surface of myeloma cells. The apoptosis inducing effect of mevastatin could be considered as a potential participant in a complex antitumor protocol.
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PMID:Mevastatin-induced apoptosis and growth suppression in U266 myeloma cells. 1527 61


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