Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Rosik, L.; Niegisch, Günter; Fischer, Ute; Jung, Manfred; Schulz, Wolfgang A.; Hoffmann, Michèle J.

doi:10.4161/cbt.28469

Cited by 38 publications

(47 citation statements)

References 68 publications

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“…Taken together, these observations might mean that inhibition of additional HDACs beyond HDAC1-3 is counterproductive in the treatment of UCC. In support of this idea, we have previously reported that specific inhibition of HDAC6 or HDAC8 does not severely impede UCC proliferation or survival [23, 30]. …”

Section: Discussionmentioning

confidence: 76%

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Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

et al. 2016

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BackgroundTargeting of class I histone deacetylases (HDACs) exerts antineoplastic actions in various cancer types by modulation of transcription, upregulation of tumor suppressors, induction of cell cycle arrest, replication stress and promotion of apoptosis. Class I HDACs are often deregulated in urothelial cancer. 4SC-202, a novel oral benzamide type HDAC inhibitor (HDACi) specific for class I HDACs HDAC1, HDAC2 and HDAC3 and the histone demethylase LSD1, shows substantial anti-tumor activity in a broad range of cancer cell lines and xenograft tumor models.AimThe aim of this study was to investigate the therapeutic potential of 4SC-202 in urothelial carcinoma (UC) cell lines.MethodsWe determined dose response curves of 4SC-202 by MTT assay in seven UC cell lines with distinct HDAC1, HDAC2 and HDAC3 expression profiles. Cellular effects were further analyzed in VM-CUB1 and UM-UC-3 cells by colony forming assay, caspase-3/7 assay, flow cytometry, senescence assay, LDH release assay, and immunofluorescence staining. Response markers were followed by quantitative real-time PCR and western blotting. Treatment with the class I HDAC specific inhibitor SAHA (vorinostat) served as a general control.Results4SC-202 significantly reduced proliferation of all epithelial and mesenchymal UC cell lines (IC50 0.15–0.51 μM), inhibited clonogenic growth and induced caspase activity. Flow cytometry revealed increased G2/M and subG1 fractions in VM-CUB1 and UM-UC-3 cells. Both effects were stronger than with SAHA treatment.ConclusionSpecific pharmacological inhibition of class I HDACs by 4SC-202 impairs UC cell viability, inducing cell cycle disturbances and cell death. Combined inhibition of HDAC1, HDAC2 and HDAC3 seems to be a promising treatment strategy for UC.Electronic supplementary materialThe online version of this article (doi:10.1007/s11523-016-0444-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 76%

“…1a). As a pan-HDAC inhibitor control, all cell lines were likewise treated with SAHA, characterized previously by our group [20, 23, 24, 30]. In the following experiments, the cells were treated generally with 0.5 and 2.5 μM 4SC-202 and 2.5 μM SAHA (approximate IC 50 in UCCs).…”

Section: Resultsmentioning

confidence: 99%

Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

et al. 2016

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“…In the following experiments, all cells were treated with 3 nmol/L romidepsin, 0.5 mmol/L givinostat, and 2.5 mmol/L SAHA (approximate IC 50 s in UCCs). Our group has characterized the impact of SAHA on UCCs previously (6,20,21). All HDAC inhibitors, most strongly romidepsin, significantly enhanced the level of acetylated histones H3 and H4 in UCCs (Fig.…”

Section: Hdac Inhibitors Selectively Targeting Hdac1 and Hdac2 Show Smentioning

confidence: 99%

“…In contrast, neither selective inhibition of HDAC8 nor HDAC6 was efficacious (20,21). We therefore sought to evaluate the efficacy of specific HDAC1 and HDAC2 inhibition in urothelial carcinoma cell lines (UCC) by either siRNA-mediated knockdown or specific pharmacologic inhibition with the class I HDAC inhibitors romidepsin (FK228; ref.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms

Pinkerneil

Hoffmann

Deenen

et al. 2016

Molecular Cancer Therapeutics

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Class I histone deacetylases HDAC1 and HDAC2 contribute to cell proliferation and are commonly upregulated in urothelial carcinoma. To evaluate whether specific inhibition of these enzymes might serve as an appropriate therapy for urothelial carcinoma, siRNA-mediated knockdown and specific pharmacologic inhibition of HDAC1 and HDAC2 were applied in urothelial carcinoma cell lines (UCC) with distinct HDAC1 and HDAC2 expression profiles. HDACs and response marker proteins were followed by Western blotting and qRT-PCR. Effects of class I HDAC suppression on UCCs were analyzed by viability, colony forming, and caspase-3/7 assays; flow cytometry, senescence and lactate dehydrogenase cytotoxicity assays; and immunofluorescence staining. Whereas single knockdowns of HDAC1 or HDAC2 were impeded by compensatory upregulation of the other isoenzyme, efficient double knockdown of HDAC1 and HDAC2 reduced proliferation by up to 80% and induced apoptosis-like cell death in all UCCs. Clonogenic growth was cell line-and HDAC-dependently reduced, with double knockdown of HDAC1 and HDAC2 being usually most efficient. Class I HDAC-specific inhibitors, especially the more specific HDAC1/2 inhibitors romidepsin and givinostat, significantly reduced proliferation of all UCCs (IC 50 , 3.36 nmol/L-4.59 mmol/L). Romidepsin and givinostat also significantly inhibited clonogenic growth of UCCs, with minor effects on nontumorigenic controls. Intriguingly, these compounds induced primarily S-phase disturbances and nonapoptotic cell death in UCCs. Thus, although both ways of inhibiting HDAC1/2 share mechanisms and efficaciously inhibit cell proliferation, their modes of action differ substantially. Regardless, combined inhibition of HDAC1/2 appears to represent a promising strategy for urothelial carcinoma therapy.Mol Cancer Ther; 15(2); 299-312. Ó2016 AACR.

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“…12 HDAC6 is especially well suited for specific inhibition, owing to its unique domain structure and mode of action, and has been suggested to provide an exceptionally suitable target for cancer therapy. 13 Rosik et al 13 evaluated the efficacy of three different HDAC6-specific inhibitors (viz., tubacin, tubastatin A [TUB-A], and ST-80) in urothelial carcinoma cells. HDACIs are able to reduce cell survival in human breast cancer cells by remodeling human epidermal growth factor receptor 2 (HER2) promoters and HER2 expression, 14 and they can induce mitochondrial reactive oxygen species (ROS) production.…”

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confidence: 99%

Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

Yuan¹,

Peng²,

Gurunathan³

2017

IJN

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Background Breast cancer is the most common malignant disease that occurs in women. Histone deacetylase (HDAC) inhibition has recently emerged as an effective and attractive target for the treatment of cancer. The aim of this study was to investigate the efficacy of a combined treatment of tubastatin A (TUB-A) and palladium nanoparticles (PdNPs) against MDA-MB-231 human breast cancer cells using two different cytotoxic agents that work by two different mechanisms, thereby decreasing the probability of chemoresistance in cancer cells and increasing the efficacy of toxicity, to provide efficient therapy for advanced stage of cancer without any undesired side effects. Methods PdNPs were synthesized using a novel biomolecule called R-phycoerythrin and characterized using various analytical techniques. The combinatorial effect of TUB-A and PdNPs was assessed by various cellular and biochemical assays and also by gene expression analysis. Results The biologically synthesized PdNPs had an average size of 25 nm and were spherical in shape. Treatment of MDA-MB-231 human breast cancer cells with TUB-A or PdNPs showed a dose-dependent effect on cell viability. The combination of 4 μM TUB-A and 4 μM PdNPs had a significant inhibitory effect on cell viability compared with either TUB-A or PdNPs alone. The combinatorial treatment also had a more pronounced effect on the inhibition of HDAC activity and enhanced apoptosis by regulating various cellular and biochemical changes. Conclusion Our results suggest that there was a strong synergistic interaction between TUB-A and PdNPs in increasing apoptosis in human breast cancer cells. These data provide an important preclinical basis for future clinical trials on this drug combination. This combinatorial treatment increased therapeutic potentials, thereby demonstrating a relevant targeted therapy for breast cancer. Furthermore, we have provided the first evidence for the combinatorial effect and mechanism of toxicity of TUB-A and PdNPs in human breast cancer cells. The novelties of the study were identification of a combination therapy that consists of suitable therapeutic molecules that kill cancer cells and also exploration of two different possible mechanisms involved to reduce chemoresistance in cancer cells.

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Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

Cited by 38 publications

References 68 publications

Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

Evaluation of the Therapeutic Potential of the Novel Isotype Specific HDAC Inhibitor 4SC-202 in Urothelial Carcinoma Cell Lines

Inhibition of Class I Histone Deacetylases 1 and 2 Promotes Urothelial Carcinoma Cell Death by Various Mechanisms

Combination of palladium nanoparticles and tubastatin-A potentiates apoptosis in human breast cancer cells: a novel therapeutic approach for cancer

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