AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

Jane, Esther P.; Premkumar, Daniel R.; Pollack, Ian F.

doi:10.1016/j.canlet.2007.06.020

Cited by 18 publications

(20 citation statements)

References 39 publications

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“…AG490 enhanced UCN-01-induced cytotoxicity by suppressing BAD phosphorylation in p53-defective cell lines that appeared to protect against UCN-01-induced cytotoxicity. 31 Because QUE-NLs and JAK/STAT pathway inhibitors such as AG490 interfere with survival signaling by different mechanisms, we reasoned that these agents might cooperate to block tumor cell proliferation and induce apoptosis. The identification of the kinases responsible for STAT3 phosphorylation via AG490 may clarify the molecular mechanism associated with QUE-NL-induced glioma cell death.…”

Section: Discussionmentioning

confidence: 99%

The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome-induced C6 glioma cell death

Wang

Chen³

et al. 2013

Cell Death Dis

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The formulation of quercetin nanoliposomes (QUE-NLs) has been shown to enhance QUE antitumor activity in C6 glioma cells. At high concentrations, QUE-NLs induce necrotic cell death. In this study, we probed the molecular mechanisms of QUE-NL-induced C6 glioma cell death and examined whether QUE-NL-induced programmed cell death involved Bcl-2 family and mitochondrial pathway through STAT3 signal transduction pathway. Downregulation of Bcl-2 and the overexpression of Bax by QUE-NL supported the involvement of Bcl-2 family proteins upstream of C6 glioma cell death. In addition, the activation of JAK2 and STAT3 were altered following exposure to QUE-NLs in C6 glioma cells, suggesting that QUE-NLs downregulated Bcl-2 mRNAs expression and enhanced the expression of mitochondrial mRNAs through STAT3-mediated signaling pathways either via direct or indirect mechanisms. There are several components such as ROS, mitochondrial, and Bcl-2 family shared by the necrotic and apoptotic pathways. Our studies indicate that the signaling cross point of the mitochondrial pathway and the JAK2/STAT3 signaling pathway in C6 glioma cell death is modulated by QUE-NLs. In conclusion, regulation of JAK2/STAT3 and ROS-mediated mitochondrial pathway agonists alone or in combination with treatment by QUE-NLs could be a more effective method of treating chemical-resistant glioma.

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Section: Discussionmentioning

confidence: 99%

The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome-induced C6 glioma cell death

Wang

Chen³

et al. 2013

Cell Death Dis

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“…We therefore questioned whether combining PKC inhibition with 17-AAG might potentiate early steps in the induction of apoptotic signaling by this mechanism. We compared the levels of the active, cleaved forms of caspase 3 and BAX in cells treated with enzastaurin and 17-AAG alone, and the two combined, using specific antibodies that recognize the respective cleaved fragments by Western immunoblotting [27]. In T98G cells, treatment with 17-AAG alone had no effect on the levels of cleaved BAX and caspase 3.…”

Section: Combined Exposure Of Glioma Cells To Enzastaurin and 17-aag mentioning

confidence: 99%

“…Total cell lysates were prepared and analyzed by Western Blot analysis as described previously [27]. Equal amounts of protein were separated by SDS-polyacrylamide gel electrophoresis and electrotransferred onto a nylon membrane (Invitrogen, Carlsbad, CA).…”

Section: Western Blotting Analysismentioning

confidence: 99%

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The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells

Jane

Pollack

2008

Cancer Letters

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Recent studies have suggested that the proliferation of malignant gliomas may result from activation of protein kinase C (PKC)-mediated pathways. Enzastaurin (LY317615), an acyclic bisindolylmaleimide, is an oral inhibitor of PKCβ as well as other isoforms. The initial objective of this study was to assess the efficacy of enzastaurin in a series of malignant human glioma cell lines with diverse genomic alterations. Although enzastaurin independently produced a dose-dependent inhibition of cellular proliferation and decreased cell viability in each of the glioma cell lines examined, and partially down-regulated Akt and GSK3β phosphorylation, median effective concentrations were at the upper limits of, or above, the clinically achievable range in all cell lines tested. We therefore examined whether the efficacy of enzastaurin could be enhanced by combination with the HSP90 antagonist, 17-AAG, which inhibits Akt and other signaling intermediates by a distinct mechanism. In comparison to the effect of enzastaurin alone, combination of enzastaurin with 17-AAG led to marked enhancement of antiproliferative and cytotoxic effects. Simultaneous exposure to both agents significantly increased the release of cytochrome c, as well as caspase 3 activation, Bax cleavage, and inhibition of Akt phosphorylation. Cells exposed to enzastaurin and 17-AAG also displayed a significant reduction in cell cycle regulatory proteins, such as CDK4 and CDK6. Taken together, these findings suggest that the efficacy of enzastaurin can be potentiated by the addition of 17-AAG, and indicate that combining molecularly targeted therapies may provide a more effective strategy than single-agent therapy to treat patients with malignant gliomas.

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“…64 It has long been suggested that the regulation of p53 activity sensitizes cells to the effects of several anticancer drugs. 65,66 More recently, the development of effective SIRT1-specific antagonists or inhibitors of SIRT family proteins and the need for potent and selective inhibitors, particularly those of SIRT1, remain to be fulfilled. 67 Among these antagonists was salermide, one of the first-discovered sirtinol analogs, which has a strong in vitro inhibitory effect on SIRT1 and SIRT2 and was shown to selectively induce apoptosis in cancer cells.…”

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confidence: 99%

Role of SIRT1-mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes

Wang¹,

Wang²,

To³

et al. 2015

IJN

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Flavonoids, the major polyphenol components in Cotinus coggygria (CC), have been found to show an anticancer effect in our previous study; however, the exact mechanisms of inducing human glioblastoma (GBM) cell death remain to be resolved. In this study, a novel polyvinylpyrrolidone K-30/sodium dodecyl sulfate and polyethyleneglycol-coated liposome loaded with CC flavonoids (CCFs) was developed to enhance solubility and the antibrain tumor effect, and the molecular mechanism regarding how CCF nanoliposomes (CCF-NLs) induce apoptotic cell death in vitro was investigated. DBTRG-05MG GBM cell lines treated with CCF-NLs showed potential antiproliferative effects. Regarding the underlying mechanisms of inducing apoptosis in DBTRG-05MG GBM cells, CCF-NLs were shown to downregulate the expression of antiapoptotic B-cell lymphoma/leukemia 2 (Bcl-2), an apoptosis-related protein family member, but the expression of proapoptotic Bcl-2-associated X protein was enhanced compared with that in controls. CCF-NLs also inhibited the activity of caspase-3 and -9, which is the initiator caspase of the extrinsic and intrinsic apoptotic pathways. Blockade of caspase activation consistently induced apoptosis and inhibited growth in CCF-NL-treated DBTRG-05MG cells. This study further investigated the role of the Akt pathway in the apoptotic cell death by CCF-NLs, showing that CCF-NLs deactivated Akt. Specifically, CCF-NLs downregulated the expression of p-Akt and SIRT1 as well as the level of phosphorylated p53. Together, these results indicated SIRT1/p53-mediated cell death was induced by CCF-NLs, but not by extracellular signal-regulated kinase, in DBTRG-05MG cells. Overall, this study suggested caspase-dependent activation of both the intrinsic and extrinsic signaling pathways, probably through blockade of the SIRT1/p53-mediated mitochondrial and Akt pathways to exert the proapoptotic effect of CCF-NLs in DBTRG-05MG GBM cells.

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AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation

Cited by 18 publications

References 39 publications

The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome-induced C6 glioma cell death

The JAK2/STAT3 and mitochondrial pathways are essential for quercetin nanoliposome-induced C6 glioma cell death

The heat shock protein antagonist 17-AAG potentiates the activity of enzastaurin against malignant human glioma cells

Role of SIRT1-mediated mitochondrial and Akt pathways in glioblastoma cell death induced by Cotinus coggygria flavonoid nanoliposomes

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