4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

Mahal, Katharina; Kahlen, Philip; Biersack, Bernhard; Schobert, Rainer

doi:10.1016/j.yexcr.2015.06.008

Cited by 8 publications

(3 citation statements)

References 68 publications

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“…This open question needs further clarification in coming experiments, as it is valuable information for predicting the Animacroxam caused a pronounced increase in apoptosisspecific caspase-3 activity in TGCT cells. This is in line with earlier findings that showed that animacroxam can induce apoptosis in certain human melanoma cells (40). The extent of caspase-3 induction by 0.6 mmol/L animacroxam exceeded by far a similar effect of vorinostat, again regardless of the cisplatin sensitivity of the investigated cell lines.…”

Section: Discussionsupporting

confidence: 92%

Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells

Steinemann

Dittmer

Kuzyniak

et al. 2017

Molecular Cancer Therapeutics

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Novel approaches for the medical treatment of advanced solid tumors, including testicular germ cell tumors (TGCT), are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual-mode compound animacroxam for TGCT treatment. Animacroxam consists of an HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell-cycle arresting, and apoptosis-inducing effects in TGCT cell lines with different cisplatin sensitivities. The IC values of animacroxam ranged from 0.22 to 0.42 μmol/L and were not correlated to the cisplatin sensitivity of the tumor cells. No unspecific cytotoxicity of animacroxam was observed in either cisplatin-sensitive or resistant TGCT cells, even at doses as high as 10 μmol/L. Furthermore, animacroxam induced the formation of actin stress fibers in cancer cells, thereby confirming the cytoskeleton-disrupting and antimigratory properties of its imidazole moiety. When compared with the clinically established HDAC inhibitor vorinostat, the novel dual-mode compound animacroxam exhibited superior antitumoral efficacy Animacroxam also reduced the tumor size of TGCT tumors, as evidenced by performing xenograft experiments on tumor bearing chorioallantoic membranes of fertilizes chicken eggs (CAM assay). The experiments also revealed a very good tolerability of the compound, and hence, animacroxam may be a promising candidate for innovative treatment of TGCT in general and the more so for platinum-insensitive or refractory TGCT..

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Section: Discussionsupporting

confidence: 92%

Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells

Steinemann

Dittmer

Kuzyniak

et al. 2017

Molecular Cancer Therapeutics

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“…Recently, we presented conjugates of imidazoles and hydroxamic acids which combine HDAC inhibition with cytoskeletal modulation [34,38,52]. However, conjugates with imidazoles derived from CA-4 had lost crucial CA-4 typical properties such as inhibition of the polymerization of tubulin.…”

Section: Discussionmentioning

confidence: 99%

Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure–Activity Relations of New Inhibitors of HDAC and/or Tubulin Function

Schmitt

Gosch

Dittmer

et al. 2019

IJMS

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New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps. While their antiproliferative and microtubule disrupting effect was most pronounced for derivatives with short spacers, HDAC inhibition was strongest for those with longer spacers. These findings were further supported by computational methods such as structure-based docking experiments exploring the target interactions of the derivatives with varying linkers. For instance, compounds featuring short four-atom spacers between cap and hydroxamic acid inhibited the growth of various cancer cell lines and human endothelial hybrid cells with IC50 values in the low nanomolar range. In line with their ability to inhibit the microtubule assembly, four- and five-atom spacered hydroxamic acids caused an accumulation of 518A2 melanoma cells in G2/M phase, whereas a compound featuring a six-atom spacer and performing best in HDAC inhibition, induced a G1 arrest in these cells. All these beneficial anticancer activities together with their selectivity for cancer cells over non-malignant cells, point out the great potential of these novel pleiotropic HDAC and tubulin inhibitors as drug candidates for cancer therapy.

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“…Our previous study has found that alterations in histone acetylation and methylation of Topo IIα promoter may result in reduced expression and activity of Topo IIα [ 12 ]. Histone deacetylases (HDACs) as a class of enzymes affect the acetylation status of histones and other vital cellular proteins, and their inhibitors such as trichostatin (TSA) and etacrox result in a dramatic increase of histone acetylation [ 17 , 18 ]. Our previous study has shown that MCP30, a mixture contains two ribosome-inactivating proteins alpha-momorcharin and beta-momorcharin isolated from bitter melon seeds, significantly inhibits the activity of HDAC-1 and promotes the acetylation of histone H3 and H4 [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Trichostatin A and MCP30 Relieve Benzene-Induced Hematotoxicity via Restoring Topoisomerase IIα

et al. 2016

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Dysfunction of histone acetylation inhibits topoisomerase IIα (Topo IIα), which is implicated in benzene-induced hematotoxicity in patients with chronic benzene exposure. Whether histone deacetylase (HDAC) inhibitors can relieve benzene-induced hematotoxicity remains unclear. Here we showed that hydroquinone, a main metabolite of benzene, increased the HDAC activity, decreased the Topo IIα expression and induced apoptosis in human bone marrow mononuclear cells in vitro, and treatment with two HDAC inhibitors, namely trichostatin A (TSA) or a mixture of ribosome-inactivating proteins MCP30, almost completely reversed these effects. We further established a benzene poisoning murine model by inhaling benzene vapor in a container and found that benzene poisoning decreased the expression and activity of Topo IIα, and impaired acetylation of histone H4 and H3. The analysis of regulatory factors of Topo IIα promoter found that benzene poisoning decreased the mRNA levels of SP1 and C-MYB, and increased the mRNA level of SP3. Both TSA and MCP30 significantly enhanced the acetylation of histone H3 and H4 in Topo IIα promoter and increased the expression and activity of Topo IIα in benzene poisoning mice, which contributed to relieve the symptoms of hematotoxicity. Thus, treatment with HDAC inhibitors represents an attractive approach to reduce benzene-induced hematotoxicity.

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4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

Cited by 8 publications

References 68 publications

Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells

Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells

Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure–Activity Relations of New Inhibitors of HDAC and/or Tubulin Function

Histone Deacetylase Inhibitors Trichostatin A and MCP30 Relieve Benzene-Induced Hematotoxicity via Restoring Topoisomerase IIα

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