Synergistic Effect of Histone Deacetylase Inhibitors FK228 and m-Carboxycinnamic Acid Bis-Hydroxamide with Proteasome Inhibitors PSI and PS-341 against Gastrointestinal Adenocarcinoma Cells

Adachi, Masaaki; Zhang, YuBin; Zhao, Xudong; Minami, Takae; Kawamura, Ryota; Hinoda, Yuji; Imai, Kohzoh

doi:10.1158/1078-0432.ccr-03-0806

Cited by 59 publications

(43 citation statements)

References 27 publications

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“…In vitro, depsipeptide induced p21 cip1 in several cell lines (30,36). Consistent with the p53 genotype, depsipeptide induced p21 cip1 in BT27 and IRS56 tumors.…”

Section: Discussionsupporting

confidence: 57%

“…However, determination of HDAC activity in the presence of inhibitor would be required to support such conjecture. In vitro, depsipeptide (5 nmol/L) increased histone acetylation after 24 hours in DLD-1 cells (30) and increased acetylation was due to inhibition of histone deacetylation, which was confirmed by determining the effects on HDAC activity (10,11). Therefore, the level of histones and histone acetylation state was investigated in tumors that were sensitive and insensitive to depsipeptide treatment.…”

Section: Discussionmentioning

confidence: 81%

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Evaluation of the Antitumor Efficacy, Pharmacokinetics, and Pharmacodynamics of the Histone Deacetylase Inhibitor Depsipeptide in Childhood Cancer Models In vivo

Graham

Tucker

Creech

et al. 2006

Clinical Cancer Research

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Purpose: Histone acetyltransferases and histone deacetylases (HDAC) control the acetylation state of histones and other proteins regulating transcription and protein function. Several structurally diverse HDAC inhibitors have been developed as cancer therapeutic agents and in vitro have been shown to cause differentiation, cell cycle arrest, or apoptosis. Here, we have evaluated depsipeptide, a natural tetrapeptide HDAC inhibitor, against a panel of pediatric solid tumor models in vivo and evaluated pharmacokinetic and pharmacodynamic variables with tumor sensitivity. Experimental Design: Depsipeptide was administered at the maximum tolerated dose (4.4 mg/kg administered every 7 days Â 3 i.v. repeated q21d for a total of two cycles) to scid mice bearing 39 independently derived childhood tumors (9 brain tumors,11kidney cancers, 9 rhabdomyosarcomas, 3 neuroblastomas, and 7 osteosarcomas). Pharmacokinetic variables were determined, as were changes in histone and p53 acetylation, induction of p53 and p53 genotype, and alterations in Akt phosphorylation. Results: Of 39 tumors evaluated, three showed objective tumor regressions [two brain tumors (primitive neuroectodermal tumor and atypical teratoid malignant rhabdoid tumor) and oneWilms' tumor]. Depsipeptide inhibited growth of many tumor lines but achieved stable disease (<25% increase in volume during treatment cycle 1) in only two tumor models (anaplastic astrocytoma, two rhabdomyosarcomas, and a Wilms' tumor). Pharmacokinetic analysis showed that the population estimated AUC 0-24 was 1,123 ng h/mL, similar to the exposure following 13 mg/m 2 in ongoing phase I trials. Pharmacodynamic changes in histone acetylation (H2A, H2B, H3, and H4) in three depsipeptide-sensitive and three intrinsically resistant tumors followed a similar pattern; maximal increases in histone acetylation occurred at 8 hours and were elevated for up to 96 hours. In two sensitive tumor lines, IRS56 and BT27 (both wild-type p53) p53 increased in treated tumors being maximal at 8 hours and associated with induction of p21 cip1 , whereas p53 was stable in tumors with mutant p53. Sensitivity to depsipeptide did not correlate with p53 genotype, p53 acetylation, cleaved poly(ADP-ribose) polymerase, or phosphorylation of Akt (Ser 473 ). Conclusions: Our results show that depsipeptide inhibits its target in vivo causing increased histone acetylation; however, this does not correlate with drug sensitivity.The relatively low objective response rate [3 of 39 (8%) tumor lines showing greater than or equal to partial response and 4 (10%) stable disease] administered at dose levels that give clinically relevant drug exposures suggests that as a single agent depsipeptide may have limited clinical utility against pediatric solid tumors in a first-line setting.

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“…In vitro, depsipeptide induced p21 cip1 in several cell lines (30,36). Consistent with the p53 genotype, depsipeptide induced p21 cip1 in BT27 and IRS56 tumors.…”

Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 81%

Evaluation of the Antitumor Efficacy, Pharmacokinetics, and Pharmacodynamics of the Histone Deacetylase Inhibitor Depsipeptide in Childhood Cancer Models In vivo

Graham

Tucker

Creech

et al. 2006

Clinical Cancer Research

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“…Anticancer compounds such as nanoparticles and chemotherapeutic agents cause malfunction of mitochondria, which in turn induce cell death in a variety of cancer cells. 34,40,57 Previously, several studies have suggested that a variety of chemotherapeutic agents such as HDACIs, 58 redox cycling agents, 59 proteasome inhibitors, 60 and silver and graphene nanoparticles induce oxidative stress in the cells and eventually lead to cell death. 34,48,61 To examine the change in intracellular ROS level caused by oxidative stress, SKOV3 cells were treated with rGO-Ag (0.20 µM) alone, TSA (0.20 µM) alone, or …”

Section: Rgo-tsa and Tsa Enhance Production Of Rosmentioning

confidence: 99%

Novel biomolecule lycopene-reduced graphene oxide-silver nanoparticle enhances apoptotic potential of trichostatin A in human ovarian cancer cells (SKOV3)

Zhang¹,

Huang²,

Zhang³

et al. 2017

IJN

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Background Recently, there has been much interest in the field of nanomedicine to improve prevention, diagnosis, and treatment. Combination therapy seems to be most effective when two different molecules that work by different mechanisms are combined at low dose, thereby decreasing the possibility of drug resistance and occurrence of unbearable side effects. Based on this consideration, the study was designed to investigate the combination effect of reduced graphene oxide-silver nanoparticles (rGO-AgNPs) and trichostatin A (TSA) in human ovarian cancer cells (SKOV3). Methods The rGO-AgNPs were synthesized using a biomolecule called lycopene, and the resultant product was characterized by various analytical techniques. The combination effect of rGO-Ag and TSA was investigated in SKOV3 cells using various cellular assays such as cell viability, cytotoxicity, and immunofluorescence analysis. Results AgNPs were uniformly distributed on the surface of graphene sheet with an average size between 10 and 50 nm. rGO-Ag and TSA were found to inhibit cell viability in a dose-dependent manner. The combination of rGO-Ag and TSA at low concentration showed a significant effect on cell viability, and increased cytotoxicity by increasing the level of malondialdehyde and decreasing the level of glutathione, and also causing mitochondrial dysfunction. Furthermore, the combination of rGO-Ag and TSA had a more pronounced effect on DNA fragmentation and double-strand breaks, and eventually induced apoptosis. Conclusion This study is the first to report that the combination of rGO-Ag and TSA can cause potential cytotoxicity and also induce significantly greater cell death compared to either rGO-Ag alone or TSA alone in SKOV3 cells by various mechanisms including reactive oxygen species generation, mitochondrial dysfunction, and DNA damage. Therefore, this combination chemotherapy could be possibly used in advanced cancers that are not suitable for radiation therapy or surgical treatment and facilitate overcoming tumor resistance and disease progression.

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“…12 Our earlier studies in pancreatic cancer models showed that disruption of aggresomes by genetic (siRNA) or pharmacologic (SAHA) inhibition of HDAC6 activity augments the anticancer activity of bortezomib. 10 The synergistic anticancer effects of simultaneous inhibition of HDACs and proteasomal activity have also been observed in other cancer models, [13][14][15][16] and this therapeutic strategy is now moving forward into clinical trials for advanced solid malignancies.The sensitivity to bortezomib and HDAC inhibitors such as SAHA relies upon active protein synthesis. 10,17 To identify patients who may most benefit from their clinical use, we further investigated what factors might regulate sensitivity to these agents.…”

mentioning

confidence: 91%

Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA

Nawrocki

Carew

Maclean

et al. 2008

Blood

110

115

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IntroductionProteasome inhibitors represent a novel class of anticancer agents that have potent anticancer activity in both preclinical and clinical settings. 1 Bortezomib (Velcade), the first proteasome inhibitor for cancer therapy, is the most clinically advanced of these agents and has received US Food and Drug Administration (FDA) approval for the treatment of multiple myeloma (MM) and mantle cell lymphoma (MCL). The great success of bortezomib in these cancers has prompted its evaluation in many other tumor models where it also displays promising in vivo antitumor activity. 2-6 Furthermore, bortezomib enhances the anticancer activity of many other conventional and novel therapeutic modalities, thus demonstrating its potential broad-based applications in cancer therapy. [7][8][9][10][11] Investigation of the mechanisms of action of bortezomib has revealed that it has pleiotropic cellular effects that contribute to its anticancer activity including growth inhibition, the induction of apoptosis in tumor and endothelial cells, the inhibition of tumor angiogenesis, and the disruption of survival signaling cascades. We have previously shown that bortezomib-mediated proteasomal inhibition results in the accumulation of large quantities of ubiquitin-conjugated proteins organized into perinuclear structures termed "aggresomes." 10 These ubiquitin aggresomes appear to form as a part of a cytoprotective response designed to handle the overwhelming protein accrual that occurs when the proteasome is inhibited in malignant but not in normal cells. The formation of aggresomes is an active process and requires histone deacetylase 6 (HDAC6) to form a bridge between microtubules and ubiquitin-conjugated proteins, enabling them to coalesce into a tightly bundled perinuclear structure. 12 Our earlier studies in pancreatic cancer models showed that disruption of aggresomes by genetic (siRNA) or pharmacologic (SAHA) inhibition of HDAC6 activity augments the anticancer activity of bortezomib. 10 The synergistic anticancer effects of simultaneous inhibition of HDACs and proteasomal activity have also been observed in other cancer models, [13][14][15][16] and this therapeutic strategy is now moving forward into clinical trials for advanced solid malignancies.The sensitivity to bortezomib and HDAC inhibitors such as SAHA relies upon active protein synthesis. 10,17 To identify patients who may most benefit from their clinical use, we further investigated what factors might regulate sensitivity to these agents. Oncogenic activation of Myc is a hallmark of nearly all rapidly dividing malignancies and Myc activation markedly up-regulates the translational machinery and thus results in an increase in protein synthesis. 18,19 Given these properties, we tested the hypothesis that the Myc family of transcription factors regulates sensitivity to the combination of bortezomib and SAHA. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From MethodsCells and cell culture NCI-H929 and U266 MM cells and human foreskin fibrobla...

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Synergistic Effect of Histone Deacetylase Inhibitors FK228 and m-Carboxycinnamic Acid Bis-Hydroxamide with Proteasome Inhibitors PSI and PS-341 against Gastrointestinal Adenocarcinoma Cells

Abstract: ABSTRACT

Cited by 59 publications

References 27 publications

Evaluation of the Antitumor Efficacy, Pharmacokinetics, and Pharmacodynamics of the Histone Deacetylase Inhibitor Depsipeptide in Childhood Cancer Models In vivo

Evaluation of the Antitumor Efficacy, Pharmacokinetics, and Pharmacodynamics of the Histone Deacetylase Inhibitor Depsipeptide in Childhood Cancer Models In vivo

Novel biomolecule lycopene-reduced graphene oxide-silver nanoparticle enhances apoptotic potential of trichostatin A in human ovarian cancer cells (SKOV3)

Myc regulates aggresome formation, the induction of Noxa, and apoptosis in response to the combination of bortezomib and SAHA

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