Valproic acid induces apoptosis in chronic lymphocytic leukemia cells through activation of the death receptor pathway and potentiates TRAIL response

Lagneaux, Laurence; Gillet, Nicolas; Stamatopoulos, Basile; Delforge, Alain; Dejeneffe, Marielle; Massy, Martine; Meuleman, Nathalie; Kentos, Alain; Martiat, Philippe; Willems, Lucas; Bron, Dominique

doi:10.1016/j.exphem.2007.06.014

Cited by 58 publications

(61 citation statements)

References 53 publications

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“…c-FLIP structurally resembles caspase-8 but lacks proteolytic activity, and it blocks death receptor-mediated signaling by preventing caspase 8 activation at the DISC formed by DR4 and/or DR5 stimulation [8]. Many previous reports have shown that HDACIs enhance TRAIL-induced apoptosis by downregulating c-FLIP in various tumor types, such as by sodium butyrate in human colon carcinoma cells [40], by VPA in primary CLL cells isolated from patients [17] and by LAQ824 in Jurkat and HL-60 ALL cells [37]. In both CCRF-CEM and CEM-CM3 cells, compared with the single agent treatments, the combination of AY4 or TRAIL with SAHA or VPA triggered much faster and more substantial decreases in c-FLIP L expression, which in turn increased caspase-8 activation and Bid cleavage to subsequently activate both the extrinsic and intrinsic apoptotic pathways.…”

Section: Discussionmentioning

confidence: 99%

“…4a). It had been previously observed that HDACIs enhance caspase-8 activation by downregulating c-FLIP, a competitive inhibitor of caspase-8 for DISC formation, in TRAILinduced apoptosis in various leukemia cell lines [17,18,20,21,37]. Those findings prompted us to determine whether SAHA and VPA, in combination with AY4 or TRAIL, can also decrease c-FLIP expression in CEM-CM3 and CCRF-CEM cells.…”

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 93%

“…Many studies have attributed synergistic cytotoxicity by combining TRAIL or anti-DR5 agonistic mAbs with HDACIs to upregulation of DR4 or DR5 expression on the cell surface [17,18,21,37]. When treated with SAHA (1 lM) or VPA (1 mM) for 24 h, both CEM-CM3 and CCRF-CEM cells exhibited little or no change in DR4 and DR5 cell surface expression levels, compared with the untreated control cells (Fig.…”

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 98%

“…1. The subtoxic dosages of each agent were very similar to those previously used in combination with TRAIL to induce synergistic cell death of various tumor cells [11,12,14,17,20,21,23]. The cells were treated for 24 h with subtoxic dosage of each chemical agent alone or in combination with either AY4 (10 lg/ml) or TRAIL (0.5 lg/ml) prior to the determination of cell viability.…”

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 99%

“…In particular, histone deacetylase inhibitors (HDACIs) have shown extensive synergistic cell death-inducing activity in combination with TRAIL [3,16]. Valproic acid (VPA) significantly increased TRAIL-sensitivity of patient-derived primary chronic lymphocytic leukemia (CLL) cells by downregulating c-FLIP [17] and in an established chronic myeloid leukemia (CML) cell line by increasing expression of DR4 and DR5 [18]. Suberoylanilide hydroxamic acid (SAHA) also augmented TRAIL-mediated cytotoxicity in various established acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML) cells by amplifying the extrinsic and intrinsic pathways [19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

et al. 2010

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Cell-death signaling through the pro-apoptotic tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, death receptor 4 (DR4) and DR5, has shown tumor-selective apoptotic activity. Here, we examine susceptibility of various leukemia cell lines (HL-60, U937, K562, CCRF-CEM, CEM-CM3, and THP-1) to an anti-DR4 agonistic monoclonal antibody (mAb), AY4, in comparison with TRAIL. While most of the leukemia cell lines were intrinsically resistant to AY4 or TRAIL alone, the two T-cell acute lymphoblastic leukemia (T-ALL) lines, CEM-CM3 and CCRF-CEM cells, underwent synergistic caspase-dependent apoptotic cell death by combination of AY4 or TRAIL with a histone deacetylase inhibitor (HDACI), either suberoylanilide hydroxamic acid (SAHA) or valproic acid (VPA). All of the combined treatments synergistically downregulated several antiapoptotic proteins (c-FLIP, Bcl-2, Bcl-X L , XIAP, and survivin) without significant changing the expression levels of pro-apoptotic proteins (Bax and Bak) or the receptors (DR4 and DR5). Downregulation of c-FLIP to activate caspase-8 was a critical step for the synergistic apoptosis through both extrinsic and intrinsic apoptotic pathways. Our results demonstrate that the HDACIs have synergistic effects on DR4-specific mAb AY4-mediated cell death in the T-ALL cells with comparable competence to those exerted by TRAIL, providing a new strategy for the targeted treatment of human T-ALL cells.

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Section: Discussionmentioning

confidence: 99%

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 93%

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 98%

Section: Responses Of Various Leukemia Cell Lines To Ay4 or Trail Alonementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

et al. 2010

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Valproic Acid Induces the Hyperacetylation of P53, Expression of P53 Target Genes, and Markers of the Intrinsic Apoptotic Pathway in Midorganogenesis Murine Limbs

Paradis

Hales

2015

Birth Defects Research Pt B

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In utero exposure to valproic acid (VPA), an anticonvulsant and histone deacetylase inhibitor (HDACi), increases the risk of congenital malformations. Although the mechanisms leading to the teratogenicity of VPA remain unsolved, several HDAC inhibitors increase cell death in cancer cell lines and embryonic tissues. Moreover, P53, the master regulator of apoptosis, is an established HDAC target. The purpose of this study was to investigate the effects of VPA on P53 signaling and markers of apoptosis during midorganogenesis in vitro limb development. Timed-pregnant CD1 mice (gestation day 12) were euthanized; embryonic forelimbs were excised and cultured in vitro for 3, 6, 12, or 24 hr in the presence or absence of VPA or valpromide (VPD), a non-HDACi analog of VPA. Quantitative RT-PCR and Western blots were used to assess the expression of candidate genes and proteins involved in P53 signaling and apoptosis. P53 hyperacetylation and a decrease (Survivin/Birc5 and Bcl2) or an increase (p21/Cdkn1a) in the expression of p53 target genes was observed only in VPA-exposed limbs. VPA exposure also triggered an increase in markers of apoptosis and DNA damage; the concentrations of cleaved caspase 9 and caspase 3, cleaved-poly (ADP-ribose) polymerase, and γ-H2AX were increased in VPA-exposed limbs. VPD treatment caused a small but significant increase in cleaved caspase 3. Thus, in vitro exposure to an HDACi such as VPA leads to P53 hyperacetylation, enhances the expression of P53 target genes, and triggers an increase in apoptosis that may contribute to teratogenicity.

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Targeting the epigenome with advanced delivery strategies for epigenetic modulators

Guha,

Jagadeesan,

Pandey

et al. 2024

Bioengineering & Transla Med

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Epigenetics mechanisms play a significant role in human diseases by altering DNA methylation status, chromatin structure, and/or modifying histone proteins. By modulating the epigenetic status, the expression of genes can be regulated without any change in the DNA sequence itself. Epigenetic drugs exhibit promising therapeutic efficacy against several epigenetically originated diseases including several cancers, neurodegenerative diseases, metabolic disorders, cardiovascular disorders, and so forth. Currently, a considerable amount of research is focused on discovering new drug molecules to combat the existing research gap in epigenetic drug therapy. A novel and efficient delivery system can be established as a promising approach to overcome the drawbacks associated with the current epigenetic modulators. Therefore, formulating the existing epigenetic drugs with distinct encapsulation strategies in nanocarriers, including solid lipid nanoparticles, nanogels, bio‐engineered nanocarriers, liposomes, surface modified nanoparticles, and polymer–drug conjugates have been examined for therapeutic efficacy. Nonetheless, several epigenetic modulators are untouched for their therapeutic potential through different delivery strategies. This review provides a comprehensive up to date discussion on the research findings of various epigenetics mechanism, epigenetic modulators, and delivery strategies utilized to improve their therapeutic outcome. Furthermore, this review also highlights the recently emerged CRISPR tool for epigenome editing.

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Valproic acid induces apoptosis in chronic lymphocytic leukemia cells through activation of the death receptor pathway and potentiates TRAIL response

Cited by 58 publications

References 53 publications

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

Histone deacetylase inhibitors synergistically potentiate death receptor 4-mediated apoptotic cell death of human T-cell acute lymphoblastic leukemia cells

Valproic Acid Induces the Hyperacetylation of P53, Expression of P53 Target Genes, and Markers of the Intrinsic Apoptotic Pathway in Midorganogenesis Murine Limbs

Targeting the epigenome with advanced delivery strategies for epigenetic modulators

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