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Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.

ABSTRACT: When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administered as a potential radiosensitiser.This phase I study for advanced gastrointestinal carcinoma was conducted in sequential patient cohorts exposed to escalating doses of vorinostat combined with standard-fractionated palliative radiotherapy to pelvic target volumes. Gene expression microarray analysis of the study patient peripheral blood mononuclear cells (PBMC) was followed by functional validation in cultured cell lines and mice treated with SAHA.PBMC transcriptional responses to vorinostat, including induction of apoptosis, were confined to the patient cohort reporting dose-limiting intestinal toxicities. At relevant SAHA concentrations, apoptotic features (annexin V staining and caspase 3/7 activation, but not poly-(ADP-ribose)-polymerase cleavage) were observed in cultured intestinal epithelial cells. Moreover, SAHA-treated mice displayed significant weight loss.The PRAVO study design implemented a strategy to explore treatment toxicity caused by an HDAC inhibitor when combined with radiotherapy and enabled the identification of apoptosis as a potential mechanism responsible for the dose-limiting effects of vorinostat. To the best of our knowledge, this is the first report deciphering mechanisms of normal tissue adverse effects in response to an HDAC inhibitor within a combined-modality treatment regimen.

SUBMITTER: Kalanxhi E

PROVIDER: S-EPMC5398387 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.

Kalanxhi Erta E Risberg Karianne K Barua Imon S IS Dueland Svein S Waagene Stein S Andersen Solveig Norheim SN Pettersen Solveig J SJ Lindvall Jessica M JM Redalen Kathrine Røe KR Flatmark Kjersti K Ree Anne Hansen AH

Cancer research and treatment 20160728 2

<h4>Purpose</h4>When integrating molecularly targeted compounds in radiotherapy, synergistic effects of the systemic agent and radiation may extend the limits of patient tolerance, increasing the demand for understanding the pathophysiological mechanisms of treatment toxicity. In this Pelvic Radiation and Vorinostat (PRAVO) study, we investigated mechanisms of adverse effects in response to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) when administe ...[more]

PMID: 27488871

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Project description:IntroductionID1, founding member of the inhibitor of differentiation (ID) family, is involved in cell population growth, apoptosis and tumourigenesis.Methods and resultsWe investigated mRNA levels of ID1 in human myeloid leukaemic cell lines and in specimens of patients with acute myeloid leukaemia (AML), using semiquantitative reverse transcription-polymerase chain reaction, and protein levels of ID1 in human myeloid leukaemic cell lines using Western blot analysis. Six of seven AML cell lines and 12 of 15 AML patient samples were found to have barely detectable ID1 mRNA. All of these cell lines showed the same levels of protein in proportion to levels of mRNA. Two of the AML cell lines with low ID1 expression, KG1 and KG-1a, were chosen for treatment with either the DNA demethylation reagent, 5-aza-2'-deoxycytidine (DAC), or the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA). These treatments were alone or in combination, and ID1 expression was induced by both DAC and TSA. No hypermethylated ID1 gene promoter was detected in the majority of the cell lines and patient specimens, by methylation-specific polymerase chain reaction, suggesting that induction of ID1 in KG1 and KG-1a was not due to direct demethylation of the ID1 gene promoter. Chromatin immunoprecipitation showed that accumulation of acetyl-histone H3 and release of HDAC1 were correlated with ID1 induction by these drugs. Flow cytometric assay demonstrated more apoptosis induced by TSA or TSA in combination with DAC, in both KG-1 and KG-1a cell lines. Increase of intracellular reactive oxygen species was observed when treated with TSA.ConclusionMost AML cell lines and human AML samples have very low levels of expression of ID1. TSA or TSA in combination with DAC is able to restore ID1 expression in low ID1-expressing AML cell lines by re-activating the aberrantly deacetylated promoter, and this also results in more apoptotic cell death, in which ID1 and the redox pathway may be involved.

Project description:BACKGROUND: Lung cancer is the leading cause of cancer mortality worldwide, yet the therapeutic strategy for advanced non-small cell lung cancer (NSCLC) is limitedly effective. In addition, validated histone deacetylase (HDAC) inhibitors for the treatment of solid tumors remain to be developed. Here, we propose a novel HDAC inhibitor, OSU-HDAC-44, as a chemotherapeutic drug for NSCLC. METHODOLOGY/PRINCIPAL FINDINGS: The cytotoxicity effect of OSU-HDAC-44 was examined in three human NSCLC cell lines including A549 (p53 wild-type), H1299 (p53 null), and CL1-1 (p53 mutant). The antiproliferative mechanisms of OSU-HDAC-44 were investigated by flow cytometric cell cycle analysis, apoptosis assays and genome-wide chromatin-immunoprecipitation-on-chip (ChIP-on-chip) analysis. Mice with established A549 tumor xenograft were treated with OSU-HDAC-44 or vehicle control and were used to evaluate effects on tumor growth, cytokinesis inhibition and apoptosis. OSU-HDAC-44 was a pan-HDAC inhibitor and exhibits 3-4 times more effectiveness than suberoylanilide hydroxamic acid (SAHA) in suppressing cell viability in various NSCLC cell lines. Upon OSU-HDAC-44 treatment, cytokinesis was inhibited and subsequently led to mitochondria-mediated apoptosis. The cytokinesis inhibition resulted from OSU-HDAC-44-mediated degradation of mitosis and cytokinesis regulators Auroroa B and survivin. The deregulation of F-actin dynamics induced by OSU-HDAC-44 was associated with reduction in RhoA activity resulting from srGAP1 induction. ChIP-on-chip analysis revealed that OSU-HDAC-44 induced chromatin loosening and facilitated transcription of genes involved in crucial signaling pathways such as apoptosis, axon guidance and protein ubiquitination. Finally, OSU-HDAC-44 efficiently inhibited A549 xenograft tumor growth and induced acetylation of histone and non-histone proteins and apoptosis in vivo. CONCLUSIONS/SIGNIFICANCE: OSU-HDAC-44 significantly suppresses tumor growth via induction of cytokinesis defect and intrinsic apoptosis in preclinical models of NSCLC. Our data provide compelling evidence that OSU-HDAC-44 is a potent HDAC targeted inhibitor and can be tested for NSCLC chemotherapy.

Dataset Information

Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.

Publications

Induction of Apoptosis in Intestinal Toxicity to a Histone Deacetylase Inhibitor in a Phase I Study with Pelvic Radiotherapy.

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