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)

Flavopiridol is a synthetic flavone, which inhibits growth in vitro and in vivo of several solid malignancies such as renal, prostate, and colon cancers. It is a potent cyclin-dependent kinase inhibitor presently in clinical trials. In this study, we examined the effect of flavopiridol on a panel of glioma cell lines having different genetic profiles: five of six have codeletion of p16(INK4a) and p14(ARF); three of six have p53 mutations; and one of six shows overexpression of mouse double minute-2 (MDM2) protein. Independent of retinoblastoma and p53 tumor suppressor pathway alterations, flavopiridol induced apoptosis in all cell lines but through a caspase-independent mechanism. No cleavage products for caspase 3 or its substrate poly(ADP-ribose) polymerase or caspase 8 were detected. The pan-caspase inhibitor Z-VAD-fmk did not inhibit flavopiridol-induced apoptosis. Mitochondrial damage measured by cytochrome c release and transmission electron microscopy was not observed in drug-treated glioma cells. In contrast, flavopiridol treatment induced translocation of apoptosis-inducing factor from the mitochondria to the nucleus. The proteins cyclin D(1) and MDM2 involved in the regulation of retinoblastoma and p53 activity, respectively, were down-regulated early after flavopiridol treatment. Given that MDM2 protein can confer oncogenic properties under certain circumstances, loss of MDM2 expression in tumor cells could promote increased chemosensitivity. After drug treatment, a low Bcl-2/Bax ratio was observed, a condition that may favor apoptosis. Taken together, the data indicate that flavopiridol has activity against glioma cell lines in vitro and should be considered for clinical development in the treatment of glioblastoma multiforme.
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PMID:Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway. 1258 31

Flavopiridol has potent anti-proliferative properties due to its direct action of binding to the ATP-binding pocket of cyclin-dependent kinases (cdks), and due to its indirect action reducing levels of other cyclins and cdk inhibitors, contributing to its pleiotropic effects. Flavopiridol is a potent apoptotic agent due to its ability to cause cell death in cycling as well as non-cycling tumor cells; to down-regulate important cell survival proteins, such as survivin, through inhibition of the phosphorylation of Thr34; to increase sensitivity for S phase cells to drug treatment by modulating E2F-1 transcription factor activity in tumor cells; to induce both caspase-dependent and -independent mitochondrial cell death pathways; and to inhibit the activation of p-Akt which in turn inhibits activation of NF-kappaB. Flavopiridol possesses several important anti-angiogenic activities including induction of apoptosis of endothelial cells; inhibition of the hypoxic induction of vascular endothelial growth factor and/or its production under hypoxic conditions through inhibition of HIF-1alpha transcription; and decreased secretion of matrix metalloproteinases that is linked with significant inhibition of invasive potential in Matrigel assays. Taken together, the anti-proliferative and anti-angiogenic properties of flavopiridol may contribute to its anti-tumor activities observed in several preclinical animal models of human cancers including prostate, lymphoid, head and neck, colon, and glioma. These promising preclinical observations opened the way for phase I and II clinical trials. Given the low toxicity profile of flavopiridol used as a single agent in patients, combination therapy now offers numerous opportunities in the near future to improve the efficacy of flavopiridol in the treatment of refractory cancers.
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PMID:Flavopiridol: pleiotropic biological effects enhance its anti-cancer activity. 1516 14

Angiogenesis is a critical step required for sustained tumor growth and tumor progression. The stimulation of endothelial cells by cytokines secreted by tumor cells such as vascular endothelial growth factor (VEGF) induces their proliferation and migration. This is a prominent feature of high-grade gliomas. The secretion of VEGF is greatly upregulated under conditions of hypoxia because of the transcription factor hypoxiainducible factor (HIF)-1alpha, which controls the expression of many genes, allowing rapid adaptation of cells to their hypoxic microenvironment. Flavopiridol, a novel cyclin-dependent kinase inhibitor, has been attributed with antiangiogenic properties in some cancer cell lines by its ability to inhibit VEGF production. Here, we show that flavopiridol treatment of human U87MG and T98G glioma cell lines decreases hypoxia-mediated HIF-1alpha expression, VEGF secretion, and tumor cell migration. These in vitro results correlate with reduced vascularity of intracranial syngeneic GL261 gliomas from animals treated with flavopiridol. In addition, we show that flavopiridol downregulates HIF-1alpha expression in the presence of a proteasome inhibitor, an agent that normally results in the accumulation and overexpression of HIF-1alpha. The potential to downregulate HIF-1alpha expression with flavopiridol treatment in combination with a proteasome inhibitor makes this an extremely attractive anticancer treatment strategy for tumors with high angiogenic activity, such as gliomas.
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PMID:Flavopiridol downregulates hypoxia-mediated hypoxia-inducible factor-1alpha expression in human glioma cells by a proteasome-independent pathway: implications for in vivo therapy. 1605 97