International Journal of Radiation Oncology*Biology*Physics
Biology contributionsModulation of radiation response by histone deacetylase inhibition
Introduction
Histone deacetylase (HDAC) inhibitors represent a class of anticancer agents that may prove effective as radiation sensitizers. HDAC inhibitors serve to regulate chromatin architecture through modification of histone tails. Histone proteins organize DNA into nucleosomes that are regular repeating structures of chromatin. The acetylation status of histones influences chromatin structure, which in turn serves to regulate gene expression. Two classes of enzymes can affect the acetylation of histones—histone acetyltransferases (HATs) and HDACs. Alterations in baseline HAT or HDAC activity have been identified in several human cancers. HDAC inhibition de-represses transcriptional activity of a set of genes that are “preprogrammed” to be responsive to changes in histone acetylation status (1, 2). HDAC inhibitors therefore promote hyperacetylation of histones, which in turn leads to chromatin relaxation and selective expression of genes that promote tumor suppression.
The rationale for combining HDAC inhibitors with radiation in cancer therapy can be considered at several levels. The combination of HDAC inhibitors with radiation may provide general therapeutic advantage because of the differential toxicity associated with each treatment modality. Further, underlying mechanisms of action for HDAC inhibitors suggest the potential for synergy with radiation deriving from physical interaction between HDAC inhibitors and chromatin architecture as well as differential expression of genes regulated by histone acetylation.
The present study explores the potential therapeutic value of combining the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) with radiation. Prostate and glioma cell lines are selected for study in light of the central role of radiation for these cancers, and the need to identify new methods to enhance local tumor control. The data confirm that treatment with SAHA reduces clonogenic survival and enhances radiation-induced apoptosis in human prostate and glioma cancer cell lines. Furthermore, potential cellular mechanisms underlying the enhanced antitumor activity are examined. Preliminary data suggest that exposure to SAHA induces differential regulation of genes involved in promitogenic and survival signaling and DNA damage repair.
Section snippets
Chemicals
Cell culture media was obtained from Life Technologies Inc. (Gaithersburg, MD). Primary antibodies against epidermal growth factor receptor (EGFR), poly(ADP-ribose) polymerase (PARP), and AKT were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA); pAKT was obtained from Cell Signaling Technologies (Beverly, MA); Rad51 and DNA-PK were obtained from Neomarker (Freemont, CA); and α-tubulin was obtained from Oncogene Research Products (Cambridge, MA). ECL+ chemiluminescence detection
SAHA inhibits cell proliferation and clonogenic capacity
We examined the antiproliferative effects of SAHA in prostate (DU145) and glioma (U373vIII) cancer cell lines. As shown in Fig. 1a, cellular proliferation was inhibited in a dose-dependent manner after a 3-day exposure to SAHA. Based on known action mechanisms of HDAC inhibitors, which involve gene regulation and biochemical differentiation (3), we hypothesized that maximal growth inhibitory effects of SAHA might be achieved after longer evaluation. We therefore examined the potential of
Discussion
Several promising HDAC inhibitors are progressing through clinical trials (2, 13, 14). HDAC inhibitor mechanisms of action suggest potential for enhancing radiation response at several levels. These include physical modifications of chromatin structure (and thus altered potential for radiation damage) and differential oncoprotein regulation after histone acetylation. This study demonstrates the capacity of the HDAC inhibitor SAHA to modulate radiation response by enhancing radiation-induced
Conclusion
The current data demonstrate the capacity of the HDAC inhibitor SAHA to enhance radiation response in prostate and glioma cells. Mechanisms of interaction may include direct interactions with chromatin structure, abrogation of key DNA damage repair processes, and attenuation of pro-survival signals which confer radiation resistance. Studies are in progress to characterize the capacity of SAHA to modulate radiation response and tumor eradication in vivo. Such studies may provide a scientific
References (40)
- et al.
Antisense inhibition of the RAD51 enhances radiosensitivity
Biochem Biophys Res Commun
(1996) - et al.
Epidermal growth factor receptor and tumor response to radiationIn vivo preclinical studies
Int J Radiat Oncol Biol Phys
(2004) - et al.
Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl
J Biol Chem
(1999) - et al.
Regulation of Rad51 function by c-Abl in response to DNA damage
J Biol Chem
(1998) - et al.
BCR/ABL regulates mammalian RecA homologs, resulting in drug resistance
Mol Cell
(2001) - et al.
Epidermal growth factor receptorAn independent predictor of survival in astrocytic tumors given definitive irradiation
Int J Radiat Oncol Biol Phys
(1996) - et al.
Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002
Int J Radiat Oncol Biol Phys
(2003) Histone-deacetylase inhibitorsNovel drugs for the treatment of cancer
Nat Rev Drug Discov
(2002)- et al.
Histone deacetylases and cancerCauses and therapies
Nat Rev Cancer
(2001) - et al.
The histone deacetylase inhibitor suberoylanilide hydroxamic acid induces differentiation of human breast cancer cells
Cancer Res
(2001)
Sensing and repairing DNA double-strand breaks
Carcinogenesis
Silencing expression of the catalytic subunit of DNA-dependent protein kinase by small interfering RNA sensitizes human cells for radiation-induced chromosome damage, cell killing, and mutation
Cancer Res
The RAS signal transduction pathway and its role in radiation sensitivity
Oncogene
Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck
Cancer Res
Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa)
Clin Cancer Res
Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, Taxotere, gemcitabine, and epothilone B
Mol Cancer Ther
Modulation of p53, ErbB1, ErbB2, and Raf-1 expression in lung cancer cells by depsipeptide FR901228
J Natl Cancer Inst
A phase I trial of depsipeptide (FR901228) in patients with advanced cancer
J Exp Ther Oncol
Phase I clinical trial of histone deacetylase inhibitorSuberoylanilide hydroxamic acid administered intravenously
Clin Cancer Res
Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation
Clin Cancer Res
Cited by (234)
HDAC1 regulates the chemosensitivity of laryngeal carcinoma cells via modulation of interleukin-8 expression
2021, European Journal of PharmacologyCitation Excerpt :It has been revealed that SAHA, a pan-HDAC inhibitor, is not effective against head and neck cancer as a single agent (Haigentz et al., 2012; Ramalingam et al., 2007). However, the combination of SAHA with chemotherapy or radiation therapy showed significantly improved therapeutic efficacy in preclinical and clinical studies (Blattmann et al., 2010; Bruzzese et al., 2011; Chinnaiyan et al., 2005; Gressette et al., 2014). Therefore, our present study, together with published data, suggest that specifically targeting HDAC1 may further improve the efficacy of chemotherapy in LSCC.
Augmenting the therapeutic window of radiotherapy: A perspective on molecularly targeted therapies and nanomaterials
2020, Radiotherapy and OncologyThe Histone Deacetylase Inhibitor Romidepsin Spares Normal Tissues While Acting as an Effective Radiosensitizer in Bladder Tumors in Vivo
2020, International Journal of Radiation Oncology Biology PhysicsImpact of epigenetic modifiers on the immune system
2020, Epigenetics of the Immune SystemPharmacological methods to transcriptionally modulate double-strand break DNA repair
2020, International Review of Cell and Molecular BiologyDNA-dependent protein kinase: Epigenetic alterations and the role in genomic stability of cancer
2019, Mutation Research - Reviews in Mutation Research