BCNU Down-Regulates Anti-Apoptotic Proteins Bcl-xL and Bcl-2 in Association with Cell Death in Oligodendroglioma-Derived Cells

Lytle, Richard A.; Jiang, Zhihong; Zheng, X.F. Steven; Rich, Keith M.

doi:10.1023/b:neon.0000033382.40601.5a

Cited by 20 publications

(12 citation statements)

References 29 publications

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“…In this observation, carmustine dose-dependently induced DWm depolarization, up-regulation of Bax, down-regulation of Bcl-2 and caspase-3 activation, providing sufficient evidence to indicate that carmustine incurred mitochondriamediated intrinsic platelet apoptosis. The data were consistent with previous reports that indicated carmustine incurred nucleated cells apoptosis by down-regulating anti-apoptotic proteins [17]. Depolarization of DWm and activation of caspase-3 are the common characteristics of apoptosis in platelets induced by various stimuli [22].…”

Section: Discussionsupporting

confidence: 92%

“…Previous studies on the neurotoxicity of carmustine have revealed that carmustine induces oxidative stress, leading to caspase-3 activation and apoptosis [15,16]. In another study, carmustine could markedly down-regulate the expression of anti-apoptotic proteins Bcl-2 and Bcl-xL in tumor cells [17]. These results indicate that carmustine induces apoptosis mainly through activating the mitochondria-mediated intrinsic apoptotic pathway.…”

Section: Introductionmentioning

confidence: 75%

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Carmustine induces platelet apoptosis

et al. 2014

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Carmustine is one of the alkylating chemotherapeutic agents, which are used to treat various types of cancers, such as brain tumors, Hodgkins and non-Hodgkins lymphoma and multiple myeloma. However, carmustine has the side effect of thrombocytopenia, and the mechanism is not completely understood. In this study, we show that carmustine dose-dependently induced depolarization of mitochondrial inner transmembrane potential (ΔΨm), up-regulation of Bax, down-regulation of Bcl-2 and caspase-3 activation. Carmustine did not induce surface expression of P-selectin or PAC-1 binding, whereas, obviously reduced collagen and thrombin-induced platelet aggregation. Dicumarol, c-Jun NH2-terminal kinase-specific inhibitor, reduced carmustine-induced ΔΨm depolarization in platelets. The numbers of circulating platelets were reduced, and the tail bleeding time was significantly increased in mice that were injected with carmustine. Taken together, these data indicate that carmustine induced platelet apoptosis, suggesting the possible pathogenesis of thrombocytopenia in patients treated with carmustine.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 75%

Carmustine induces platelet apoptosis

et al. 2014

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“…Moreover, silencing HSF1 exacerbated the decrease in Bcl-X L levels by HNE. The specific down-regulation of Bcl-X L is recently emerging as a consequence of exposure of cells to chemotherapeutics, including cisplatin, bischloronitrosourea (carmustine), retinoic acid as well as to UV light (55)(56)(57)(58). Our finding that HSF1-mediated gene expression stabilizes Bcl-X L levels implies that activation of the heat shock response may partly mediate chemotherapeutic resistance.…”

Section: Discussionmentioning

confidence: 79%

Heat Shock Factor 1 Attenuates 4-Hydroxynonenal-mediated Apoptosis

Jacobs

Marnett

2007

Journal of Biological Chemistry

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Lipid peroxidation is a consequence of both normal physiology and oxidative stress that generates various reactive metabolites, a principal end product being 4-hydroxynonenal (HNE). As a diffusible electrophile, HNE reacts extensively with cellular nucleophiles. Consequently, HNE alters cellular signaling and activates the intrinsic apoptotic cascade. We have previously demonstrated that in addition to promoting apoptosis, HNE activates stress response pathways, including the antioxidant, endoplasmic reticulum stress, DNA damage, and heat shock responses. Here we demonstrate that activation of the heat shock response by HNE is dependent on the expression and nuclear translocation of heat shock factor 1 (HSF1), which promotes the expression of heat shock protein 40 (Hsp40) and Hsp70-1. Ectopic expression and immunoprecipitation of c-Myc-tagged Hsp70-1 indicates that HNE disrupts the inhibitory interaction between Hsp70-1 and HSF1, leading to the activation heat shock gene expression. Using siRNA to silence HSF1 expression, we observe that HSF1 is necessary for the induction of Hsp40 and Hsp70-1 by HNE, and the lack of Hsp expression is correlated with an increase in apoptosis. Nrf2, the transcription factor that mediates the antioxidant response, was also silenced using siRNA. Silencing Nrf2 also enhanced the cytotoxicity of HNE, but not as effectively as HSF1. Silencing HSF1 expression facilitates the activation of JNK pro-apoptotic signaling and selectively decreases expression of the anti-apoptotic Bcl-2 family member Bcl-X L . Overexpression of Bcl-X L attenuates HNEmediated apoptosis in HSF1-silenced cells. Overall, activation of HSF1 and stabilization of Bcl-X L mediate a protective response that may contribute significantly to the cellular biology of lipid peroxidation.The oxidation of membrane phospholipids is an inescapable consequence of normal cellular respiration. A major route for lipid oxidation involves the abstraction of bis-allylic hydrogen atoms from polyunsaturated fatty acids by reactive oxygen species. The resulting lipid radicals react readily with dioxygen to form lipid hydroperoxides, which are mainly reduced to their corresponding hydroxyl species. A number of xenobiotic metabolites, anti-neoplastic drugs, transition metals, and disease states promote increased levels of both reactive oxygen species and oxidized lipids. The decomposition of oxidized lipids yields a variety of diffusible electrophiles, including the ␣,␤-unsaturated aldehyde, 4-hydroxynonenal (HNE).2 Diffusible lipid electrophiles are capable of modifying nucleophilic sites on DNA and proteins throughout the cell. Modification of cellular targets by HNE is found in multiple disease states, including atherosclerosis, ischemia-reperfusion injury, Parkinson disease, and Alzheimer disease (1-5). Plasma conjugates of HNE have been observed at low micromolar concentrations in healthy adults, implying the detectable generation of HNE under normal physiological conditions, although absolute steady-state concentrations are less clea...

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“…After overnight stirring at room temperature, the solution was diluted with ethyl acetate and washed with saturated NaHCO 3 aqueous solution and brine. The organic layer was dried over MgSO 4 , filtered, and evaporated under reduced pressure. The residue was purified by SiO 2 chromatography to give the title compound as a white solid (0.24 g, 52% …”

Section: Methodsmentioning

confidence: 99%

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

Choi

Khosla

et al. 2005

Molecular Cancer Therapeutics

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Tissue transglutaminase 2 belongs to a family of transglutaminase proteins that confers mechanical resistance from proteolysis and stabilizes proteins. Transglutaminase 2 promotes transamidation between glutamine and lysine residues with the formation of covalent linkages between proteins. Transglutaminase 2 also interacts and forms complexes with proteins important in extracellular matrix organization and cellular adhesion. We have identified the novel finding that treatment of glioblastoma cells with transglutaminase 2 inhibitors promotes cell death and enhances sensitivity to chemotherapy. Treatment with either the competitive transglutaminase 2 inhibitor, monodansylcadaverine, or with highly specific small-molecule transglutaminase 2 inhibitors, KCA075 or KCC009, results in induction of apoptosis in glioblastoma cells. Treatment with these transglutaminase 2 inhibitors resulted in markedly decreased levels of the prosurvival protein, phosphorylated Akt, and its downstream targets. These changes promote a proapoptotic profile with altered levels of multiple intracellular proteins that determine cell survival. These changes include decreased levels of the antiapoptotic proteins, survivin, phosphorylated Bad, and phosphorylated glycogen synthetase kinase 3B (GSK-3B), and increased levels of the proapoptotic BH3-only protein, Bim. In vivo studies with s.c. murine DBT glioblastoma tumors treated with transglutaminase 2 inhibitors combined with the chemotherapeutic agent, N-NV -bis (2-chloroethyl)-N-nitrosourea (BCNU), decreased tumor size based on weight by 50% compared with those treated with BCNU alone. Groups treated with transglutaminase 2 inhibitors showed an increased incidence of apoptosis determined with deoxynucleotidyl transferasemediated biotin nick-end labeling staining. These studies identify inhibition of transglutaminase 2 as a potential target to enhance cell death and chemosensitivity in glioblastomas. [Mol Cancer Ther 2005;4(9):1293 -302]

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BCNU Down-Regulates Anti-Apoptotic Proteins Bcl-xL and Bcl-2 in Association with Cell Death in Oligodendroglioma-Derived Cells

Cited by 20 publications

References 29 publications

Carmustine induces platelet apoptosis

Carmustine induces platelet apoptosis

Heat Shock Factor 1 Attenuates 4-Hydroxynonenal-mediated Apoptosis

Tissue transglutaminase 2 inhibition promotes cell death and chemosensitivity in glioblastomas

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