Interstrand Crosslink Repair as a Target for HDAC Inhibition

Nikolova, Teodora; Kiweler, Nicole; Krämer, Oliver

doi:10.1016/j.tips.2017.05.009

Cited by 48 publications

(47 citation statements)

References 95 publications

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“…These data encouraged us to test for a dysregulation of DNA repair factors and DNA injury upon class I HDAC inhibition in primary human RCC cells (Mz-ccRCC2). We found that MS-275 reduced the expression of the recombinase RAD51, which is a key factor for HR-mediated DNA repair (Nikolova et al 2017), in primary RCC cells ( Fig. 1d).…”

Section: Hdaci Suppress Dna Repair Protein Expressionmentioning

confidence: 78%

“…HDACi are epigenetic drugs that enhance protein acetylation and thereby impact a large number of cellular functions (Bayat Mokhtari et al 2017;Mrakovcic et al 2019;Müller and Krämer 2010;Nikolova et al 2017;Vancurova et al 2018). Since the Food and Drug Administration has approved four HDACi for the treatment of hematological malignancies, additional research is warranted to demonstrate how a pharmacological inactivation of HDACs affects metastasis formation.…”

Section: Figmentioning

confidence: 99%

“…Due to these findings, we analyzed the phosphorylation of histone H2AX at serine-139 (ɣH2AX), which is a marker for replication stress, single-/double-strand breaks in DNA, and apoptosis (Nikolova et al 2017;Rogakou et al 1998). MS-275 and VPA, which we used as additional class I HDACi (Bradner et al 2010;Müller and Krämer 2010), induced a time-and dose-dependent accumulation of ɣH2AX ( Fig.…”

Section: Hdaci Suppress Dna Repair Protein Expressionmentioning

confidence: 99%

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Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes

Kiweler

Wünsch

Wirth

et al. 2020

J Cancer Res Clin Oncol

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Purpose We set out to determine whether clinically tested epigenetic drugs against class I histone deacetylases (HDACs) affect hallmarks of the metastatic process. Methods We treated permanent and primary renal, lung, and breast cancer cells with the class I histone deacetylase inhibitors (HDACi) entinostat (MS-275) and valproic acid (VPA), the replicative stress inducer hydroxyurea (HU), the DNA-damaging agent cis-platinum (L-OHP), and the cytokine transforming growth factor-β (TGFβ). We used proteomics, quantitative PCR, immunoblot, single cell DNA damage assays, and flow cytometry to analyze cell fate after drug exposure. Results We show that HDACi interfere with DNA repair protein expression and trigger DNA damage and apoptosis alone and in combination with established chemotherapeutics. Furthermore, HDACi disrupt the balance of cell adhesion protein expression and abrogate TGFβ-induced cellular plasticity of transformed cells. Conclusion HDACi suppress the epithelial-mesenchymal transition (EMT) and compromise the DNA integrity of cancer cells. These data encourage further testing of HDACi against tumor cells.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Hdaci Suppress Dna Repair Protein Expressionmentioning

confidence: 78%

Section: Figmentioning

confidence: 99%

Section: Hdaci Suppress Dna Repair Protein Expressionmentioning

confidence: 99%

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Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes

Kiweler

Wünsch

Wirth

et al. 2020

J Cancer Res Clin Oncol

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“…Moreover, HDAC functions are protective against DNA damage, and depletion or inhibition of HDACs impair DNA damage repair mechanisms, rendering cells more susceptible to DNA-damaging agents (Miller et al 2010). Recent evidence illustrates that HDAC inhibitors themselves propel DNA damage through replicative stress and a reduction of DNA repair proteins (Nikolova et al 2017). HDACs are validated targets in anti-tumoral therapy and, to date, five HDAC inhibitors (panobinostat, romidepsin, belinostat, vorinostat and chidamide) have been approved for the treatment of hematological malignancies (Bates et al 2015; Cheng et al 2015; Mann et al 2007; O’Connor et al 2015; Shi et al 2015).…”

Section: Introductionmentioning

confidence: 99%

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

et al. 2018

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High histone deacetylase (HDAC) 8 and HDAC10 expression levels have been identified as predictors of exceptionally poor outcomes in neuroblastoma, the most common extracranial solid tumor in childhood. HDAC8 inhibition synergizes with retinoic acid treatment to induce neuroblast maturation in vitro and to inhibit neuroblastoma xenograft growth in vivo. HDAC10 inhibition increases intracellular accumulation of chemotherapeutics through interference with lysosomal homeostasis, ultimately leading to cell death in cultured neuroblastoma cells. So far, no HDAC inhibitor covering HDAC8 and HDAC10 at micromolar concentrations without inhibiting HDACs 1, 2 and 3 has been described. Here, we introduce TH34 (3-(N-benzylamino)-4-methylbenzhydroxamic acid), a novel HDAC6/8/10 inhibitor for neuroblastoma therapy. TH34 is well-tolerated by non-transformed human skin fibroblasts at concentrations up to 25 µM and modestly impairs colony growth in medulloblastoma cell lines, but specifically induces caspase-dependent programmed cell death in a concentration-dependent manner in several human neuroblastoma cell lines. In addition to the induction of DNA double-strand breaks, HDAC6/8/10 inhibition also leads to mitotic aberrations and cell-cycle arrest. Neuroblastoma cells display elevated levels of neuronal differentiation markers, mirrored by formation of neurite-like outgrowths under maintained TH34 treatment. Eventually, after long-term treatment, all neuroblastoma cells undergo cell death. The combination of TH34 with plasma-achievable concentrations of retinoic acid, a drug applied in neuroblastoma therapy, synergistically inhibits colony growth (combination index (CI) < 0.1 for 10 µM of each). In summary, our study supports using selective HDAC inhibitors as targeted antineoplastic agents and underlines the therapeutic potential of selective HDAC6/8/10 inhibition in high-grade neuroblastoma.Electronic supplementary materialThe online version of this article (10.1007/s00204-018-2234-8) contains supplementary material, which is available to authorized users.

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“…Future plans are focused on the evaluation of this combination in other kinds of cancers such as ER(+) and BRCA1 mutated TNBC. 123 The combination of platinum-based compounds/HDACi against non-small-cell lung carcinoma (NSCLC) founded its rationale mainly in two findings: (i) HDACs play the main role in resistance and adaptation to genotoxic treatment in different ways [127][128][129][130][131][132][133][134] ; (ii) platinum chemotherapy is the first choice for the treatment of such tumors. [135][136][137] A dose escalation phase I clinical study was conducted for panobinostat 6/etoposide/cisplatin triple combination.…”

mentioning

confidence: 99%

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

Tomaselli

Lucidi

Rotili

et al. 2019

Medicinal Research Reviews

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Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.

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Interstrand Crosslink Repair as a Target for HDAC Inhibition

Cited by 48 publications

References 95 publications

Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes

Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes

The HDAC6/8/10 inhibitor TH34 induces DNA damage-mediated cell death in human high-grade neuroblastoma cell lines

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

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