Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition

Flatmark, Kjersti; Nome, Ragnhild V.; Folkvord, Sigurd; Bratland, Åse; Rasmussen, Heidi; Ellefsen, Mali Strand; Fodstad, Øystein; Ree, Anne Hansen

doi:10.1186/1748-717x-1-25

Cited by 45 publications

(25 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A similar strategy can be used to inhibit HAT enzymes. There are already numerous reports in the literature demonstrating that inhibition of HDAC or HAT activity can sensitize tumor cells to ionizing radiation [83][84][85][86][87][88][89][90]. However, whether the activity is due to inhibition of DNA damage response genes remains to be fully assessed.…”

Section: Epigenetic Gene Expression Modulators As Part Of a Treatmentmentioning

confidence: 99%

DNA Damage Repair and Response Proteins as Targets for Cancer Therapy

Lieberman¹

2008

CMC

View full text Add to dashboard Cite

The cellular response to DNA damage is critical for determining whether carcinogenesis, cell death or other deleterious biological effects will ensue. Numerous cellular enzymatic mechanisms can directly repair damaged DNA, or allow tolerance of DNA lesions, and thus reduce potential harmful effects. These processes include base excision repair, nucleotide excision repair, nonhomologous end joining, homologous recombinational repair and mismatch repair, as well as translesion synthesis. Furthermore, DNA damage-inducible cell cycle checkpoint systems transiently delay cell cycle progression. Presumably, this allows extra time for repair before entry of cells into critical phases of the cell cycle, an event that could be lethal if pursued with damaged DNA. When damage is excessive apoptotic cellular suicide mechanisms can be induced. Many of the survival-promoting pathways maintain genomic integrity even in the absence of exogenous agents, thus likely processing spontaneous damage caused by the byproducts of normal cellular metabolism. DNA damage can initiate cancer, and radiological as well as chemical agents used to treat cancer patients often cause DNA damage. Many genes are involved in each of the DNA damage processing mechanisms, and the encoded proteins could ultimately serve as targets for therapy, with the goal of neutralizing their ability to repair damage in cancer cells. Therefore, modulation of DNA damage responses coupled with more conventional radiotherapy and chemotherapy approaches could sensitize cancer cells to treatment. Alteration of DNA damage response genes and proteins should thus be considered an important though as of yet not fully exploited avenue to enhance cancer therapy.

show abstract

Section: Epigenetic Gene Expression Modulators As Part Of a Treatmentmentioning

confidence: 99%

DNA Damage Repair and Response Proteins as Targets for Cancer Therapy

Lieberman¹

2008

CMC

View full text Add to dashboard Cite

show abstract

“…One of the potential clinical applications of HDACIs is to improve radiotherapy treatment, a treatment that more than 60% of all cancer patients will receive [5]. Preclinical studies have indicated that a number of HDAC inhibitors are effective radiosensitizers [6], agents that sensitize tumor cells to radiotherapy, in a variety of solid malignancies such as colorectal cancer [7] and prostate cancer cells [8]. However, the radiosensitization effects have been associated with only mild improvements in efficacy.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

Wang¹,

Min²,

Palm³

et al. 2015

Biomaterials

View full text Add to dashboard Cite

Histone deacetylase inhibitors (HDACIs) represent a class of promising agents that can improve radiotherapy in cancer treatment. However, the full therapeutic potential of HDACIs as radiosensitizers has been restricted by limited efficacy in solid malignancies. In this study, we report the development of nanoparticle (NP) formulations of HDACIs that overcome these limitations, illustrating their utility to improve the therapeutic ratio of the clinically established first generation HDACI vorinostat and a novel second generation HDACI quisinostat. We demonstrate that NP HDACIs are potent radiosensitizers in vitro and are more effective as radiosensitizers than small molecule HDACIs in vivo using mouse xenograft models of colorectal and prostate carcinomas. We found that NP HDACIs enhance the response of tumor cells to radiation through the prolongation of γ-H2AX foci. Our work illustrates an effective method for improving cancer radiotherapy treatment.

show abstract

“…PCI-24781, along with other HDAC inhibitors also in clinical development, represent a promising class of anticancer therapy agents (4,5). In addition to evidence of efficacy as a monotherapy, some HDAC inhibitors have been shown to inhibit tumor growth synergistically when administered together with ionizing radiation (IR) or with DNA-interacting cancer drugs in preclinical models (6)(7)(8)(9)(10)(11)(12). It has been suggested that the mechanism of the synergy may involve the inhibition of DNA double-strand break (DSB) repair, because after cellular irradiation, HDAC inhibition enhances and prolongs the phosphorylation of histone H2AX, a well characterized marker of DNA DSBs (13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination

Adimoolam

Sirisawad²,

Chen³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

211

179

View full text Add to dashboard Cite

Chromatin structure is regulated, in part, by affecting the acetylation of lysine residues on the amino-terminal tails of nucleosomal histones. The acetylation state of histones is maintained by the opposing actions of histone acetyl transferase and histone deacetylase (HDAC) enzymes. There are 11 known isoforms in the classic HDAC family, denoted HDAC 1-11 (1). In addition to histones, HDAC enzymes are known to deacetylate other proteins, including ␣-tubulin (2), suggesting complex, multifunctional roles for HDACs in vivo.PCI-24781 (formerly CRA-024781) is a broad-spectrum phenyl hydroxamic acid HDAC inhibitor currently being evaluated in phase I clinical trials in patients with neoplastic disease (3). The compound is a specific inhibitor of multiple HDAC isoforms that potently inhibits tumor growth in vivo with acceptable toxicity. PCI-24781, along with other HDAC inhibitors also in clinical development, represent a promising class of anticancer therapy agents (4, 5). In addition to evidence of efficacy as a monotherapy, some HDAC inhibitors have been shown to inhibit tumor growth synergistically when administered together with ionizing radiation (IR) or with DNA-interacting cancer drugs in preclinical models (6-12). It has been suggested that the mechanism of the synergy may involve the inhibition of DNA double-strand break (DSB) repair, because after cellular irradiation, HDAC inhibition enhances and prolongs the phosphorylation of histone H2AX, a well characterized marker of DNA DSBs (13-17).In mammalian cells, DSBs are repaired by one of two genetically distinct processes, known as nonhomologous end joining (NHEJ) or homologous recombination (HR) (18). NHEJ is the simpler, but more error-prone mechanism, in which the DNA ends are recognized and bound by the Ku heterodimer, which recruits DNA-PK and other proteins to directly ligate the two DNA termini. By comparison, HR is a process of greater accuracy and complexity, requiring the presence of a sister chromatid to serve as a template for repair. HR begins with strand recognition and nucleolytic processing by the MRE11-RAD50-NBS1 (MRN) complex, followed by strand invasion, branch migration, and Holliday junction formation (18,19). Both strand invasion and branch migration are initiated by RAD51, a recA homolog that binds MRN-generated ssDNA, forming nucleoprotein filaments essential for recombinational repair. After exposure to IR, RAD51 rapidly forms a complex with BRCA2 and other proteins that stimulate RAD51-mediated strand exchange and the assembly of subnuclear foci characteristic of HR (20,21). Cells lacking functional RAD51 are unable to form foci and are significantly more sensitive to IR (22). In addition to repair of IR-induced DNA damage, recent evidence suggests that RAD51 (and HR) is involved in the repair of DNA DSBs produced by cisplatin and other platinum agents (23, 24) and also in the repair of DSBs produced by stalled replication forks (25), such as those produced by inhibitors of poly(ADP-ribose) polymerase (PARP) (26)(27)(28).In the pr...

show abstract

Radiosensitization of colorectal carcinoma cell lines by histone deacetylase inhibition

Cited by 45 publications

References 44 publications

DNA Damage Repair and Response Proteins as Targets for Cancer Therapy

DNA Damage Repair and Response Proteins as Targets for Cancer Therapy

Nanoparticle formulations of histone deacetylase inhibitors for effective chemoradiotherapy in solid tumors

HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination

Contact Info

Product

Resources

About