Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wound-healing assay-guided fractionation of an EtOAc extract of the fungal strain Fusarium oxysporum EPH2RAA endophytic in Ephedra fasciculata afforded beauvericin (1), (-)-oxysporidinone (2), and two new N-methyl-2-pyridones, (-)-4,6'-anhydrooxysporidinone (3) and (-)-6-deoxyoxysporidinone (4). Beauvericin (1) inhibited migration of the metastatic prostate cancer (PC-3M) and breast cancer (MDA-MB-231) cells and showed antiangiogenic activity in HUVEC-2 cells at sublethal concentrations. Cytotoxicity-guided fractionation of an EtOAc extract of F. oxysporum strain CECIS occurring in Cylindropuntia echinocarpus afforded rhodolamprometrin (5), bikaverin (6), and the new natural product 6-deoxybikaverin (7). All compounds were evaluated for cytotoxicity in a panel of four sentinel cancer cell lines, NCI-H460 (non-small-cell lung), MIA Pa Ca-2 (pancreatic), MCF-7 (breast), and SF-268 (CNS glioma), and only beauvericin (1) and bikaverin (6) were active, with 1 and 6 showing selective toxicity toward NCI-H460 and MIA Pa Ca-2, respectively. Interestingly, 6-deoxybikaverin (7) was completely devoid of activity, suggesting the requirement of the C-6 hydroxy group of bikaverin for its cytotoxic activity.
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PMID:Search for cell motility and angiogenesis inhibitors with potential anticancer activity: beauvericin and other constituents of two endophytic strains of Fusarium oxysporum. 1728 29

In 1999, Maniotis reported that blood vessels of highly aggressive uveal melanomas are formed by tumor cells instead of endothelial cells. He termed this novel concept in tumor vascularization vasculogenic mimicry (VM). Since then, VM has been seen in several malignant tumor types such as breast cancer, liver cancer, glioma, ovarian cancer, melanoma, prostate cancer, and bidirectional differentiated malignant tumors. Laser scanning confocal angiography, electron microscopy, and three-dimensional cell culture have confirmed the existence of VM. The molecular mechanisms that underlie VM are not fully clear, but metalloproteinases via their cleavage of laminin, VE-cadherin by promoting adherence of the VM channel wall to tumor cells, tumor cell dedifferentiation, and tumor microenvironment have been shown to play a role in VM. Zhang and co-workers have proposed a three-stage phenomenon among VM channels, mosaic blood vessels, and endothelium-dependent blood vessels, wherein all three patterns participate in tumor blood supply. Therapeutic strategies that target endothelial cells have no effect on tumor cells that engage in VM. VM-targeting strategies include suppressing tyrosine kinase activity and using a knockout EphA2 gene, downregulating VE-cadherin, using antibodies against human MMPs and the laminin 5gamma2 chain, and using anti-PI3K therapy. We review here the current status of research on VM; discuss molecular mechanisms of VM, factors affecting VM formation, and its clinical significance; and explore the development of novel tumor-targeted treatments that are based on the biochemical and molecular events that regulate VM.
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PMID:Vasculogenic mimicry: current status and future prospects. 1730 54

The developmentally important Hedgehog (Hh) signaling pathway has recently been implicated in several forms of solid cancer. Current drug development programs focus on targeting the protooncogene Smoothened, a key transmembrane pathway member. These drug candidates, albeit promising, do not address the scenario in which pathway activation occurs downstream of Smoothened, as observed in cases of medulloblastoma, glioma, pericytoma, breast cancer, and prostate cancer. A cellular screen for small-molecule antagonists of GLI-mediated transcription, which constitutes the final step in the Hh pathway, revealed two molecules that are able to selectively inhibit GLI-mediated gene transactivation. We provide genetic evidence of downstream pathway blockade by these compounds and demonstrate the ineffectiveness of upstream antagonists such as cyclopamine in such situations. Mechanistically, both inhibitors act in the nucleus to block GLI function, and one of them interferes with GLI1 DNA binding in living cells. Importantly, the discovered compounds efficiently inhibited in vitro tumor cell proliferation in a GLI-dependent manner and successfully blocked cell growth in an in vivo xenograft model using human prostate cancer cells harboring downstream activation of the Hh pathway.
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PMID:Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. 1749 66

Toward the goal of developing an optical imaging contrast agent that will enable surgeons to intraoperatively distinguish cancer foci from adjacent normal tissue, we developed a chlorotoxin:Cy5.5 (CTX:Cy5.5) bioconjugate that emits near-IR fluorescent signal. The probe delineates malignant glioma, medulloblastoma, prostate cancer, intestinal cancer, and sarcoma from adjacent non-neoplastic tissue in mouse models. Metastatic cancer foci as small as a few hundred cells were detected in lymph channels. Specific binding to cancer cells is facilitated by matrix metalloproteinase-2 (MMP-2) as evidenced by reduction of CTX:Cy5.5 binding in vitro and in vivo by a pharmacologic blocker of MMP-2 and induction of CTX:Cy5.5 binding in MCF-7 cells following transfection with a plasmid encoding MMP-2. Mouse studies revealed that CTX:Cy5.5 has favorable biodistribution and toxicity profiles. These studies show that CTX:Cy5.5 has the potential to fundamentally improve intraoperative detection and resection of malignancies.
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PMID:Tumor paint: a chlorotoxin:Cy5.5 bioconjugate for intraoperative visualization of cancer foci. 1763 99

Wilms tumors (WTs) have a complex etiology, displaying genetic and epigenetic changes, including loss of imprinting (LOI) and tumor suppressor gene silencing. To identify new regions of epigenetic perturbation in WTs, we screened kidney and tumor DNA using CpG island (CGI) tags associated with cancer-specific DNA methylation changes. One such tag corresponded to a paralog of the glioma pathogenesis-related 1/related to testis-specific, vespid, and pathogenesis proteins 1 (GLIPR1/RTVP-1) gene, previously reported to be a tumor-suppressor gene silenced by hypermethylation in prostate cancer. Here we report methylation analysis of the GLIPR1/RTVP-1 gene in WTs and normal fetal and pediatric kidneys. Hypomethylation of the GLIPR1/RTVP-1 5'-region in WTs relative to normal tissue is observed in 21/24 (87.5%) of WTs analyzed. Quantitative analysis of GLIPR1/RTVP-1 expression in 24 WTs showed elevated transcript levels in 16/24 WTs (67%), with 12 WTs displaying in excess of 20-fold overexpression relative to fetal kidney (FK) control samples. Immunohistochemical analysis of FK and WT corroborates the RNA expression data and reveals high GLIPR1/RTVP-1 in WT blastemal cells together with variable levels in stromal and epithelial components. Hypomethylation is also evident in the WT precursor lesions and nephrogenic rests (NRs), supporting a role for GLIPR1/RTVP-1 deregulation early in Wilms tumorigenesis. Our data show that, in addition to gene dosage changes arising from LOI and hypermethylation-induced gene silencing, gene activation resulting from hypomethylation is also prevalent in WTs.
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PMID:Hypomethylation and aberrant expression of the glioma pathogenesis-related 1 gene in Wilms tumors. 1803 Mar 65

There is a large number of effective cytotoxic drugs whose side effect profile, efficacy, and long-term use in man are well understood and documented over decades of use in clinical routine e.g. in the treatment of recurrent glioblastoma multiforme (GBM) and the hormone-refractory prostate cancer (HRPC). Both cancers are insensitive against most chemotherapeutic interventions; they have low response rates and poor prognoses. Some cytotoxic agents can be significantly improved by using modern technology of drug delivery or formulation. We succeeded to enhance the pharmacologic potency with simultaneous reduction of unwanted adverse reactions of the highly efficient chemotherapeutic temozolomide (TMZ) as an example. The TMZ connection to transporter molecules (TMZ-BioShuttle) resulted in a much higher pharmacological effect in glioma cell lines while using reduced doses. This permits the conclusion that a suitable chemistry could realize the ligation of pharmacologically active, but sensitive and highly unstable pharmaceutical ingredients without functional deprivation. The re-formulation of TMZ to TMZ-BioShuttle achieved a nearly 10-fold potential of the established pharmaceutic TMZ far beyond the treatment of brain tumors cells and results in an attractive reformulated drug with enhanced therapeutic index.
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PMID:TMZ-BioShuttle--a reformulated temozolomide. 1879 9

Scutellaria is a traditional herbal remedy with potential anti-cancer activity. The purpose of this study was to evaluate anticancer mechanisms of thirteen Scutellaria species and analyze their leaf, stem and root extracts for levels of common biologically active flavonoids: apigenin, baicalein, baicalin, chrysin, scutellarein, and wogonin. Malignant glioma, breast carcinoma and prostate cancer cells were used to determine tumor-specific effects of Scutellaria on cell proliferation, apoptosis and cell cycle progression, via the MTT assay and flow cytometry-based apoptosis and cell cycle analysis. The extracts and individual flavonoids inhibited the proliferation of malignant glioma and breast carcinoma cells without affecting primary or non-malignant cells. The flavonoids exhibited different mechanisms of anti-tumor activity as well as positive interactions. The antitumor mechanisms involved induction of apoptosis and cell cycle arrest at G1/G2. Of the extracts tested, leaf extracts of S. angulosa, S. integrifolia, S. ocmulgee and S. scandens were found to have strong anticancer activity. This study provides basis for further mechanistic and translational studies into adjuvant therapy of malignant tumors using Scutellaria leaf tissues.
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PMID:In vitro antitumor mechanisms of various Scutellaria extracts and constituent flavonoids. 1903 66

Short interfering RNA targeting ILK (ILK siRNA) could be used to treat patients with cancers where constitutive activation of the AKT/PI3K pathway is prominent (e.g., those cancers lack functional PTEN). It is generally believed that siRNA therapeutics will require the use of delivery systems and lipid-based formulations containing cationic lipids (CLs) are a viable option. However, CLs are known to be toxic and exposure to CLs can influence cell survival pathways. This study characterized how CLs combine with ILK siRNA to influence the AKT/PI3K pathway. Using PTEN-negative cell lines (PC3 castration-insensitive prostate cancer cells and U251 glioma cancer cells), the influence of CLs on the downstream consequences of ILK silencing was determined. When comparing nucleofection (an electroporation method that does not require the use of CLs) and CLs as means to deliver ILK siRNA, a 12- to 30-fold increase in siRNA delivery was achieved when using a CL formulation, yet ILK suppression was less efficient. Importantly, time-dependent signaling consequences associated with ILK silencing, including suppression of phosphorylated (serine 473)-AKT and changes in mTOR expression, were observed independently of ILK suppression when the target cells were exposed to cationic lipids following nucleofection-based delivery of ILK siRNA.
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PMID:siRNA-mediated integrin-linked kinase suppression: nonspecific effects of siRNA/cationic liposome complexes trigger changes in the expression of phosphorylated-AKT and mTOR independently of ILK silencing. 1928 9

Prostate cancer is one of the most common malignant cancers in men. Recent studies have shown that microRNA-21 (miR-21) is overexpressed in various types of cancers including prostate cancer. Studies on glioma, colon cancer cells, hepatocellular cancer cells and breast cancer cells have indicated that miR-21 is involved in tumor growth, invasion and metastasis. However, the roles of miR-21 in prostate cancer are poorly understood. In this study, the effects of miR-21 on prostate cancer cell proliferation, apoptosis, and invasion were examined. In addition, the targets of miR-21 were identified by a reported RISC-coimmunoprecipitation-based biochemical method. Inactivation of miR-21 by antisense oligonucleotides in androgen-independent prostate cancer cell lines DU145 and PC-3 resulted in sensitivity to apoptosis and inhibition of cell motility and invasion, whereas cell proliferation were not affected. We identified myristoylated alanine-rich protein kinase c substrate (MARCKS), which plays key roles in cell motility, as a new target in prostate cancer cells. Our data suggested that miR-21 could promote apoptosis resistance, motility, and invasion in prostate cancer cells and these effects of miR-21 may be partly due to its regulation of PDCD4, TPM1, and MARCKS. Gene therapy using miR-21 inhibition strategy may therefore be useful as a prostate cancer therapy.
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PMID:MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. 1930 77

Inhibition of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is an appealing method for decreasing the immunoresistance and augmenting T cell-mediated immunotherapy. A major impediment to this strategy is the impact of conventional PI3K/mTOR pathway inhibitors on T cell function. In particular, rapamycin, is a well-known immunosuppressant that can decrease the activity of the PI3K/mTOR pathway in tumor cells, but also has a profound inhibitory effect on T cells. Here we show that Honokiol, a natural dietary product isolated from an extract of seed cones from Magnolia grandiflora, can decrease PI3K/mTOR pathway-mediated immunoresistance of glioma, breast and prostate cancer cell lines, without affecting critical proinflammatory T cell functions. Specifically, we show that at doses sufficient to down-regulate levels of phospho-S6 and the negative immune regulator B7-H1 in tumor cells, Honokiol does not significantly impair T cell proliferation or proinflammatory cytokine production. In contrast to classic inhibitors, including LY294002, wortmannin, AKT inhibitor III and rapamycin, Honokiol specifically decreases the PI3K/mTOR pathway activity in tumor cells, but not in freshly stimulated T cells. Collectively, our data define a unique application for Honokiol and provide the impetus to more fully elucidate the mechanism by which T cells are resistant to the effects of this particular inhibitor. Honokiol is clinically available for human testing and may serve to augment T cell-mediated cancer immunotherapy.
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PMID:Honokiol-mediated inhibition of PI3K/mTOR pathway: a potential strategy to overcome immunoresistance in glioma, breast, and prostate carcinoma without impacting T cell function. 2063 86


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