Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Kim, Eun Hee; Kim, Hee Sue; Kim, Seung Up; Noh, Eun Joo; Lee, Jong-Soo; Choi, Kyeong Sook

doi:10.1038/sj.onc.1208851

Cited by 72 publications

(54 citation statements)

References 58 publications

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“…However, of major interest was our finding that apoptosis and therapeutic activity, mediated by the combination of MD5-1 and vorinostat, was also significantly suppressed by CrmA and c-FLIP, whereas overexpression of Bcl-2 had little or no effect. These data clearly demonstrated that vorinostat enhanced the apoptotic activity of MD5-1 in the extrinsic pathway and is consistent with other studies that make similar conclusions (25,26). However, there are other reports indicating that synergistic tumor cell apoptosis, mediated by the combination of HDACi and TRAIL activating agents, requires both the extrinsic and intrinsic pathways (27)(28)(29).…”

Section: Discussionsupporting

confidence: 82%

“…However, a recent study provides compelling evidence that although HDACi can indeed induce expression of TRAIL and/or its cognate receptors, this event is not necessary to mediate synergistic apoptosis of target cells by using a combination of HDACi and recombinant TRAIL or anti-DR4/DR5 mAbs (33). Other studies have correlated synergistic tumor cell apoptosis by HDACi and activators of the TRAIL pathway with decreased expression of c-FLIP (8,25), decreased expression of apoptosis inhibitors and Bcl-2 (25), inhibition of Cdc2 protein and subsequent down-regulation of survivin and XIAP (26), and modulation of NF-B activity (28,34,35). It is not yet clear whether a common molecular event will be identified as being requisite to mediate synergistic apoptosis by HDACi and TRAIL activators, or whether the responses will depend on the cell type and/or HDACi under investigation.…”

Section: Discussionmentioning

confidence: 99%

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Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Frew

Lindemann

Martin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

128

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Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Frew

Lindemann

Martin

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

128

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“…Previously, HDACI-mediated sensitization to TRAIL has been described in various solid and hematological cancer cell lines, 36 --40 including one report in glioblastoma. 41 In the present study, we show for the first time that MS275 enhances TRAILinduced apoptosis in primary cultured glioblastoma cells in addition to several established cell lines. Our data proposing MS275 as a suitable combination partner for TRAIL are supported by a recent publication showing that MS275 as single agent inhibits the growth of glioma-derived neurospheres.…”

Section: Discussionmentioning

confidence: 85%

Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP

et al. 2012

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Glioblastoma is the most common primary brain tumor with a very poor prognosis, calling for novel treatment strategies. Here, we provide first evidence that histone deacetylase inhibitors (HDACI) prime glioblastoma cells for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) -induced apoptosis at least in part by c-myc-mediated downregulation of cellular FLICE-inhibitory protein (cFLIP). Pretreatment with distinct HDACI (MS275, suberoylanilide hydroxamic acid, valproic acid) significantly enhances TRAIL-induced apoptosis in several glioblastoma cell lines. Monitoring a panel of apoptosisregulatory proteins revealed that MS275 reduces the expression of cFLIP L and cFLIP S . This leads to decreased recruitment of cFLIP L and cFLIP S and increased activation of caspase-8 to the TRAIL death-inducing signaling complex, resulting in enhanced cleavage of caspase-8, -9 and -3 and caspase-dependent apoptosis. Also, MS275 promotes TRAIL-triggered processing of Bid, activation of Bax, loss of mitochondrial membrane potential and release of cytochrome c. MS275-mediated downregulation of cFLIP occurs at the mRNA level independent of proteasome-or caspase-mediated degradation, and is preceded by upregulation of nuclear levels of c-myc, a transcriptional repressor of cFLIP. Notably, MS275 causes increased binding of c-myc to the cFLIP promoter and reduces cFLIP promoter activity. Indeed, knockdown of c-myc partially rescues cFLIP L from MS275-inferred downregulation and significantly decreases TRAIL-and MS275-induced apoptosis. Also, overexpression of cFLIP L or cFLIP S significantly reduces MS275-and TRAIL-induced apoptosis. Importantly, MS275 sensitizes primary cultured glioblastoma cells towards TRAIL and cooperates with TRAIL to reduce long-term clonogenic survival of glioblastoma cells and to suppress glioblastoma growth in vivo underscoring the clinical relevance of this approach. Thus, these findings demonstrate that HDACI represent a promising strategy to prime glioblastoma for TRAIL-induced apoptosis by targeting cFLIP.

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“…When TRAIL cross-links with its death receptors, DR4 or DR5, the death receptors oligomerize and trigger the recruitment of Fas-Associated protein with Death Domain (FADD), the activation of caspase-8, and the subsequent initiation of apoptosis (Kischkel et al, 2000). However, recent studies have shown that many cancer cells, including glioma cells, are resistant to TRAILinduced apoptosis even though they express TRAIL receptors (Hao et al, 2001;Kim et al, 2005). Thus, the development of new therapeutic strategies to restore TRAIL-induced apoptosis in cancer cells will be required to improve the efficacy of TRAIL-based cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Paxilline enhances TRAIL-mediated apoptosis of glioma cellsviamodulation of c-FLIP, survivin and DR5

Kang

Kim

et al. 2011

Exp Mol Med

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Abbreviations: FADD, fas-associated protein with death domain; TRAIL, tumor necrosis factor-related apoptosis-induced ligand AbstractTumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells while sparing normal cells. However, many cancer cells are resistant to TRAIL-induced cell death. Here, we report that paxilline, an indole alkaloid from Penicillium paxilli, can sensitize various glioma cells to TRAIL-mediated apoptosis. While treatment with TRAIL alone caused partial processing of caspase-3 to its p20 intermediate in TRAIL-resistant glioma cell lines, co-treatment with TRAIL and subtoxic doses of paxilline caused complete processing of caspase-3 into its active subunits. Paxilline treatment markedly upregulated DR5, a receptor of TRAIL, through a CHOP/GADD153-mediated process. In addition, paxilline treatment markedly downregulated the protein levels of the short form of the cellular FLICE-inhibitory protein (c-FLIP S ) and the caspase inhibitor, survivin, through proteasome-mediated degradation. Taken together, these results show that paxilline effectively sensitizes glioma cells to TRAIL-mediated apoptosis by modulating multiple components of the death receptor-mediated apoptotic pathway. Interestingly, paxilline/TRAIL co-treatment did not induce apoptosis in normal astrocytes, nor did it affect the protein levels of CHOP, DR5 or survivin in these cells. Thus, combined treatment regimens involving paxilline and TRAIL may offer an attractive strategy for safely treating resistant gliomas.

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Sodium butyrate sensitizes human glioma cells to TRAIL-mediated apoptosis through inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP

Cited by 72 publications

References 58 publications

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist

Histone deacetylase inhibitors sensitize glioblastoma cells to TRAIL-induced apoptosis by c-myc-mediated downregulation of cFLIP

Paxilline enhances TRAIL-mediated apoptosis of glioma cellsviamodulation of c-FLIP, survivin and DR5

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