Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague‐Dawley rats and Dutch Belted rabbits

Wise, L. David; Turner, Katie J.; Kerr, Janet S.

doi:10.1002/bdrb.20104

Cited by 32 publications

(32 citation statements)

References 46 publications

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“…Vorinostat (suberoylanilide hydroxamic acid; Zolinza) is a hydroxamic acid HDACI that has shown preliminary preclinical evidence of activity in hepatoma and other malignancies with a C max of ϳ9 M; however, the agent has a very short half-life in plasma and steady-state drug levels in many patients are ϳ1 M or less (Pang and Poon, 2007;Venturelli et al, 2007;Wise et al, 2007). Treatment of pancreatic tumor cells (PANC1, MiaPaca2, ASPC-1) with concentrations of vorinostat and sorafenib that are sustainable in patient serum resulted in a greater than additive increase in tumor cell killing as assessed by short-term death assays (nuclear fragmentation by 4,6-diamidino-2-phenylindole stain; trypan blue exclusion) and a synergistic increase in killing assessed by colony formation assays performed using median dose effect isobologram analyses (Fig.…”

Section: Resultsmentioning

confidence: 99%

BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate Killing

Martin¹,

Park²,

Mitchell³

et al. 2009

Mol Pharmacol

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We examined whether the multikinase inhibitor sorafenib and histone deacetylase inhibitors (HDACI) interact to kill pancreatic carcinoma cells and determined the impact of inhibiting BCL-2 family function on sorafenib and HDACI lethality. The lethality of sorafenib was enhanced in pancreatic tumor cells in a synergistic fashion by pharmacologically achievable concentrations of the HDACIs vorinostat or sodium valproate. Overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s) or knockdown of CD95 suppressed the lethality of the sorafenib/HDACI combination (sorafenib ϩ HDACI). In immunohistochemical analyses or using expression of fluorescence-tagged proteins, treatment with sorafenib and vorinostat together (sorafenib ϩ vorinostat) promoted colocalization of CD95 with caspase 8 and CD95 association with the endoplasmic reticulum markers calnexin, ATG5, and Grp78/BiP. In cells lacking CD95 expression or in cells expressing c-FLIP-s, the lethality of sorafenib ϩ HDACI exposure was abolished and was restored when cells were coexposed to BCL-2 family inhibitors [ethyl [2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)]-4H-chromene-3-carboxylate (HA14-1), obatoclax (GX15-070)]. Knockdown of BCL-2, BCL-XL, and MCL-1 recapitulated the effects of GX15-070 treatment. Knockdown of BAX and BAK modestly reduced sorafenib ϩ HDACI lethality but abolished the effects of GX15-070 treatment. Sorafenib ϩ HDACI exposure generated a CD95-and Beclin1-dependent protective form of autophagy, whereas GX15-070 treatment generated a Beclin1-dependent toxic form of autophagy. The potentiation of sorafenib ϩ HDACI killing by GX15-070 was suppressed by knockdown of Beclin1 or of BAX ϩ BAK. Our data demonstrate that pancreatic tumor cells are susceptible to sorafenib ϩ HDACI lethality and that in tumor cells unable to signal death from CD95, use of a BCL-2 family antagonist facilitates sorafenib ϩ HDACI killing via autophagy and the intrinsic pathway.In the United States, pancreatic carcinomas have 5-year survival rates of less than 5% (Bardeesy and DePinho, 2002;Parkin et al., 2005). This statistic emphasizes the need to develop original therapies using novel targeted agents against this lethal malignancy.Tumor cells use a wide variety of mechanisms to maintain cell viability, including loss of death receptor expression (e.g., CD95) by reducing expression of proapoptotic BH3 domain proteins (e.g., BAX) or by increasing expression of antiapoptotic BCL-2 family members (e.g., MCL-1) (Lessene et al.,

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Section: Resultsmentioning

confidence: 99%

BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate Killing

Martin¹,

Park²,

Mitchell³

et al. 2009

Mol Pharmacol

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“…With respect to combinatorial drug studies with a multikinase inhibitor such as sorafenib, HDACIs are of interest in that they have potential to down-regulate multiple oncogenic kinases by interfering with 90-kDa heat shock protein function, leading to proteasomal degradation of these proteins. Vorinostat (suberoylanilide hydroxamic acid; Zolinza) is a hydroxamic acid HDACI that has shown preliminary preclinical evidence of activity in hepatoma and other malignancies with a C max of ϳ9 M (Pang and Poon, 2007;Venturelli et al, 2007;Wise et al, 2007).…”

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confidence: 99%

Sorafenib and Vorinostat Kill Colon Cancer Cells by CD95-Dependent and -Independent Mechanisms

Walker

Mitchell²,

Park³

et al. 2009

Mol Pharmacol

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We examined the interaction between the multikinase inhibitor sorafenib and histone deacetylase inhibitors. Sorafenib and vorinostat synergized (sorafenib ϩ vorinostat) to kill HCT116 and SW480 cells. In SW480 cells, sorafenib ϩ vorinostat increased CD95 plasma membrane levels and promoted deathinducing signal complex (DISC) formation, and drug toxicity was blocked by knockdown of CD95 or overexpression of cellular FLICE-like inhibitory protein (c-FLIP-s). In SW620 cells that are patient-matched to SW480 cells, sorafenib ϩ vorinostat toxicity was significantly lower, which correlated with a lack of CD95 activation and lower expression of ceramide synthase 6 (LASS6). Overexpression of LASS6 in SW620 cells enhanced drug-induced CD95 activation and enhanced tumor cell killing, whereas knockdown of LASS6 in SW480 cells suppressed CD95 activation. Knocking down LASS6 expression also suppressed CD95 activation in hepatoma, pancreatic, and ovarian cancer cells. In HCT116 cells, sorafenib ϩ vorinostat treatment caused DISC formation without reducing c-FLIP-s expression and did not increase CD95 plasma membrane levels; sorafenib ϩ vorinostat exposure killed HCT116 cells via an intrinsic pathway/caspase 9-dependent mechanism. In HCT116 cells, knockdown of CD95 enhanced sorafenib ϩ vorinostat lethality, which correlated with less drug-induced CD95-dependent autophagy. Sorafenib ϩ vorinostat treatment activated the c-Jun NH 2 -terminal kinase pathway, which was causal in promoting dissociation of Beclin1 from BCL-2, and in promoting autophagy. Knockdown of Beclin1 expression blocked autophagy and enhanced drug toxicity. Our data demonstrate that treatment of colon cancer cells with sorafenib ϩ vorinostat activates CD95 via de novo ceramide synthesis that promotes viability via autophagy or degrades survival via either the extrinsic or intrinsic pathways.In the United States, colon cancer is diagnosed in ϳ150,000 patients each year, and there are ϳ50,000 deaths from the disease, which has a 5-year survival rate of ϳ60% (Parkin et al., 2005;Hegde et al., 2008). However, for patients with nonlocalized tumor at diagnosis, the 5-year survival rate is ϳ10%.The Raf-MEK1/2-ERK1/2 pathway is frequently dysregulated in neoplastic transformation Dent, 2005;Valerie et al., 2007). The MEK1/2-ERK1/2 module comprises, along with c-Jun NH 2 -terminal kinase (JNK1/2) and p38 MAPK, members of the MAPK superfamily. These kinases are involved in responses to diverse mitogens and environmental stresses and have also been implicated in cell survival processes. Activation of the ERK1/2 pathway is often associated with cell survival, whereas JNK1/2 and p38 MAPK pathway signaling often causes apoptosis. Although

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“…Vorinostat (suberoylanilide hydroxamic acid, SAHA, Zolinza ™ ) is an FDA approved hydroxamic acid HDACI that has shown preliminary pre-clinical evidence of activity in hepatoma and other malignancies with a Cmax of ~9 μM. 29–31 Sorafenib and vorinostat interact to kill in renal, pancreatic, and hepatocellular carcinoma cells via activation of the CD95 extrinsic apoptotic pathway, and reduced expression of c-FLIP-s. 24 The observation that sorafenib and vorinostat exposure causes a ligand-independent activation of CD95 to promote cell death is of particular interest to our laboratories because our prior studies show that bile acids such as deoxycholic acid (DCA) can promote ligand-independent activation of CD95 that played a role in DCA-induced cell killing and DCA-induced regulation of enzymes which control cholesterol 7 α-hydroxylase expression. 2,32–34 In one study we discovered that expression of the cyclin-dependent kinase inhibitor (CDKI) p21 Cip-1/WAF1/mda6 (p21) in primary hepatocytes enhances bile acid toxicity, and argue that this effect, too, is CD95-dependent.…”

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confidence: 99%

Regulation of autophagy by ceramide-CD95-PERK signaling

Park¹,

Zhang²,

Norris³

et al. 2008

Autophagy

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The manuscripts by Park et al.1 and Zhang et al.2 were initially planned as studies to understand the regulation of cell survival in transformed cells treated with sorafenib and vorinostat, and in primary hepatocytes treated with a bile acid+MEK1/2 inhibitor. In both cell systems we discovered that the toxicity of sorafenib and vorinostat or bile acid+MEK1/2 inhibitor exposure depended on the generation of ceramide and the ligand-independent activation of the CD95 death receptor, with subsequent activation of pro-caspase 8. We noted, however, in these systems that, in parallel with death receptor–induced activation of the extrinsic pathway, CD95 signaling also promoted increased phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) and eIF2α, increased expression of ATG5, and increased processing of LC3 and vesicularization of a GFP-LC3 construct. The knockdown of ATG5 expression blocked GFP-LC3 vesicularization and enhanced cell killing. Thus ceramide-CD95 signaling promoted cell death via activation of pro-caspase 8 and cell survival via autophagy. PERK was shown to signal in a switch-hitting fashion; PERK promoted CD95-DISC formation and an eIF2α-dependent reduction in c-FLIP-s levels that were essential for cell killing to proceed, but in parallel it also promoted autophagy that was protective. The death receptor-induced apoptosis and autophagy occur proximal to the receptor rather than the mitochondrion, and the relative flow of death receptor signaling into either pathway may determine cell fate. Finally, death receptor induced apoptosis and autophagy could be potential targets for therapeutic intervention.

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Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague‐Dawley rats and Dutch Belted rabbits

Cited by 32 publications

References 46 publications

BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate Killing

BCL-2 Family Inhibitors Enhance Histone Deacetylase Inhibitor and Sorafenib Lethality via Autophagy and Overcome Blockade of the Extrinsic Pathway to Facilitate Killing

Sorafenib and Vorinostat Kill Colon Cancer Cells by CD95-Dependent and -Independent Mechanisms

Regulation of autophagy by ceramide-CD95-PERK signaling

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