Intrinsic and Extrinsic Apoptotic Pathway Signaling as Determinants of Histone Deacetylase Inhibitor Antitumor Activity

Matthews, Geoffrey M.; Newbold, Andrea; Johnstone, Ricky W.

doi:10.1016/b978-0-12-394387-3.00005-7

Cited by 100 publications

(86 citation statements)

References 118 publications

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“…Apoptotic pathways include two major signaling routes: the extrinsic death receptor pathway and the intrinsic mitochondrial pathway (29,30). Apoptosis was mainly controlled by caspases, a family of intracellular cysteine proteases, which were grouped into initiators (caspase-2, -8, -9, and -10) and effectors (caspase-3, -6, and -7) (31,32).…”

Section: Discussionmentioning

confidence: 99%

Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer

Wang

Jiang

et al. 2016

J. Thorac. Dis.

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Background: A retrospective analysis of patients undergoing cancer surgery suggested that using local anesthetics could reduce cancer recurrence and improve survival rate. Previous studies have indicated that local anesthetics may induce apoptosis in several kinds of cells in vitro, but the mechanism is unclear. Methods: Cell viability was analyzed by MTS; reactive oxygen species (ROS), mitochondrial membrane potential (MMP, ∆Ψm), cell cycle distribution, and cell apoptosis assay were detected by flow cytometry; DNA damage was measured by comet assay; cell invasion and migration were observed by microscopy; The expression level of related proteins was detected by western blot assay. Results: The results indicated that lidocaine and ropivacaine could decrease viability, induce G0/G1 phase arrest and apoptosis in human non-small cell lung cancer (NSCLC) cells A549 and H520. Invasion and migration were suppressed. Western blot indicated the related apoptotic pathways proteins changed accordingly. Additionally, lidocaine and ropivacaine downregulated ∆Ψm, provoked DNA damage, upregulated ROS production and activated mitogen-activated protein kinase (MAPK) pathways in A549 and H520 cells. Conclusions:The cytotoxic effect of amide-linked local anesthetics on NSCLC cells were mainly due to apoptosis. The antitumor mechanism of lidocaine and ropivacaine may involve apoptotic pathways and MAPK pathways.

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Section: Discussionmentioning

confidence: 99%

Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer

Wang

Jiang

et al. 2016

J. Thorac. Dis.

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“…The development of novel therapeutic options, including proteasome inhibitors and IMiDs, has improved treatment outcomes, however, patients often develop relapsed and refractory MM, thus requiring alternative treatment approaches. Histone acetyltransferases and histone deacetylases (HDACs) control the acetylation status of proteins and affect a broad array of physiologic processes involved in cell growth and survival, including cell cycle, apoptosis and protein folding (9). The observation that HDACs may be involved in various hematological malignancies, including MM, has led to the development of HDAC inhibitors (HDACIs) as potential antitumor agents.…”

Section: Discussionmentioning

confidence: 99%

“…The observation that histone deacetylases (HDAC) may be involved in various types of hematologic malignancy has led to the development of HDAC inhibitors as potential antitumor agents (9). VPA, as one type of HDACI, has the unique advantage of oral dosage, and can achieve its effective concentration with low toxicity, providing a useful tool for investigating the mechanism of the HDAC inhibitor.…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

Wang

Zhang

2012

Molecular Medicine Reports

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Abstract. The aim of the present study was to investigate the synergistic effects of valproic acid (VPA) and arsenic trioxide (ATO) on the proliferation of RPMI8226 cells and the possible underlying mechanisms. Cell apoptosis was assessed by flow cytometry. The mRNA expression levels were analyzed by semi-quantitative polymerase chain reaction, and the protein expression levels were analyzed by western blotting. The histone acetylation and methylation states of the gene promoters were detected using a chromatin immunoprecipitation technique. The apoptotic rates of the RPMI8226 cells in the combined drug groups were significantly increased compared with those of the single drug groups (P<0.05). The mRNA and protein expression levels of Bcl-2 and the expression levels of HDAC1 mRNA and H3K9me2 protein decreased significantly in the combined groups compared with the single drug groups. The mRNA and protein expression levels of Bax, Caspase 8, Caspase 9 and LSD1, and the protein expression of acetylated H3 increased significantly in the combination groups compared with the single drug groups. Histone methylation and acetylation of the Bcl-2 and bax gene promoters were increased in the combination groups compared with the single drug groups. VPA and ATO had synergistic effects on the proliferation of RPMI8226 cells, which may have been associated with the decreased expression of Bcl-2 and the increased expression levels of Bcl-2-associated X protein, Caspase 8 and Caspase 9. Therefore, the expression levels of the Bcl-2 gene family may have been regulated by the levels of gene promoter methylation and acetylation. IntroductionMultiple myeloma (MM) is a plasma cell disorder, characterized by anemia, renal disease, lytic bone disease, and immune dysfunction. MM is one of the most common types of hematological malignancy in China (1). Although currently approved treatments for newly diagnosed MM, including high-dose chemotherapy followed by autologous transplantation, and novel drugs, including proteasome inhibitors and immunomodulatory agents (IMiDs), have led to increased survival rates, the majority of patients will eventually relapse and become refractory to treatment (2). Therefore, patients with relapsed or refractory MM have an unmet requirement for safe and efficacious novel therapies.Arsenic trioxide (ATO) has been suggested as an option for the treatment of relapsing or refractory MM. In vitro, ATO has been found to induced myeloma cell apoptosis, and monotherapy with ATO results in partial response rates between 0 and 17%, and minimal responses between 7 and 33%, resulting in mean overall response rates of 30% for treatment of myeloma (3-5).In order to improve the treatment response rates in patients with MM, ATO has been combined with other novel drugs, including proteasome inhibitors, IMiDs and dexamethsone, for the treatment of MM. The overall response rates in these combined regimens vary widely between 12 and 100% (6-8). It is necessary to identify novel combinations of ATO with other drugs, to offer nov...

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“…A synthetic lethal interaction between GLI1 knockdown and vorinostat treatment resulted in changes in expression of genes that directly regulate apoptosis. 3,32 Many studies have demonstrated the ability of HDACi to regulate apoptosis gene expression in favor of apoptosis and this is important in HDACi mechanism of action (reviewed in Bolden et al 3 and Falkenberg and Johnstone 33 ). Although vorinostat treatment alone induced gene expression changes in HCT116-VR cells in favor of apoptosis, these were clearly not sufficient to induce cell death.…”

Section: Discussionmentioning

confidence: 99%

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

et al. 2016

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Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells to vorinostat-induced apoptosis. A synthetic lethal functional screen using a whole-genome protein-coding RNAi library was used to identify genes that when knocked down cooperated with vorinostat to induce tumor cell apoptosis in otherwise resistant cells. Through iterative screening, we identified 10 vorinostatresistance candidate genes that sensitized specifically to vorinostat. One of these vorinostat-resistance genes was GLI1, an oncogene not previously known to regulate the activity of HDACi. Treatment of vorinostat-resistant cells with the GLI1 smallmolecule inhibitor, GANT61, phenocopied the effect of GLI1 knockdown. The mechanism by which GLI1 loss of function sensitized tumor cells to vorinostat-induced apoptosis is at least in part through interactions with vorinostat to alter gene expression in a manner that favored apoptosis. Upon GLI1 knockdown and vorinostat treatment, BCL2L1 expression was repressed and overexpression of BCL2L1 inhibited GLI1-knockdown-mediated vorinostat sensitization. Taken together, we present the identification and characterization of GLI1 as a new HDACi resistance gene, providing a strong rationale for development of GLI1 inhibitors for clinical use in combination with HDACi therapy.

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Intrinsic and Extrinsic Apoptotic Pathway Signaling as Determinants of Histone Deacetylase Inhibitor Antitumor Activity

Cited by 100 publications

References 118 publications

Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer

Amide-linked local anesthetics induce apoptosis in human non-small cell lung cancer

Synergistic effects of valproic acid and arsenic trioxide on RPMI8226 cells in vitro and the possible underlying mechanisms

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

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