Anticancer properties of chimeric HDAC and kinase inhibitors

Biersack, Bernhard; Polat, Síbel; Höpfner, Michael

doi:10.1016/j.semcancer.2020.11.005

Cited by 43 publications

(35 citation statements)

References 108 publications

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“…The chimeric dual kinase/HDAC inhibitor CUDC-101 has already undergone clinical trials in patients with various solid tumors. The results were very promising, underlining the high relevance of this compound class [4].…”

Section: Discussionmentioning

confidence: 93%

“…This would explain the enhanced overall anti-EGFR effect of the chimeric compounds compared to that of gefitinib alone. This could also be interesting for appraising expected/unexpected side effects, as well as therapeutic efficacy and therapy resistance [4].…”

Section: Discussionmentioning

confidence: 99%

“…In the development of novel chimeric inhibitors, the hybridization of histone deacetylase inhibitors with receptor tyrosine kinase inhibitory pharmacophores has emerged as a particularly promising anticancer approach [4]. Histone deacetylases (HDACs), which are overexpressed in various cancers, are epigenetic regulators of chromatin condensation and decondensation.…”

Section: Introductionmentioning

confidence: 99%

“…Some HDAC inhibitors, such as the hydroxamic acid derivatives vorinostat or panobinostat, are already approved for the treatment of hematologic cancer diseases and are currently under intensive investigation for their use in solid tumors [5]. There are also drawbacks of the clinical application of single HDAC inhibitors, such as intrinsic or acquired drug resistance [4]. These may be overcome by merging an HDAC-inhibitory pharmacophore with another tumor-relevant inhibitor.…”

Section: Introductionmentioning

confidence: 99%

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Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors

Goehringer

Biersack

Peng

et al. 2021

IJMS

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New chimeric inhibitors targeting the epidermal growth factor (EGFR) and histone deacetylases (HDACs) were synthesized and tested for antineoplastic efficiency in solid cancer (prostate and hepatocellular carcinoma) and leukemia/lymphoma cell models. The most promising compounds, 3BrQuin-SAHA and 3ClQuin-SAHA, showed strong inhibition of tumor cell growth at one-digit micromolar concentrations with IC50 values similar to or lower than those of clinically established reference compounds SAHA and gefitinib. Target-specific EGFR and HDAC inhibition was demonstrated in cell-free kinase assays and Western blot analyses, while unspecific cytotoxic effects could not be observed in LDH release measurements. Proapoptotic formation of reactive oxygen species and caspase-3 activity induction in PCa and HCC cell lines DU145 and Hep-G2 seem to be further aspects of the modes of action. Antiangiogenic potency was recognized after applying the chimeric inhibitors on strongly vascularized chorioallantoic membranes of fertilized chicken eggs (CAM assay). The novel combination of two drug pharmacophores against the EGFR and HDACs in one single molecule was shown to have pronounced antineoplastic effects on tumor growth in both solid and leukemia/lymphoma cell models. The promising results merit further investigations to further decipher the underlying modes of action of the novel chimeric inhibitors and their suitability for new clinical approaches in tumor treatment.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors

Goehringer

Biersack

Peng

et al. 2021

IJMS

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“…Both parent compounds act on different targets and therefore the chimeric inhibitors are able to simultaneously regulate multiple pathways. Importantly, the chimeric drugs mostly do not cause drug resistance or additive toxicity often observed in the combination therapy [ 199 , 200 ]. One of the developed anticancer hybridized HDAC inhibitor is CUDC-101 composed of hydroxamic acid linked with the quinazoline core of erlotinib acting as a receptor (EGFR and HER2) tyrosine kinase inhibitor [ 201 ].…”

Section: Chimeric Hdac-based Inhibitorsmentioning

confidence: 99%

Vorinostat (SAHA) and Breast Cancer: An Overview

Wawruszak

Borkiewicz

Okon

et al. 2021

Cancers

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Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made, high toxicity to normal cells, serious side effects, and the occurrence of multi-drug resistance limit the effective therapy of BC patients. Therefore, new active agents which improve the effectiveness of currently used regimens are highly needed. This manuscript analyzes preclinical and clinical trials data of SAHA, applied individually or in combination with other anticancer agents, considering different histological subtypes of BC.

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New chimeric HDAC inhibitors for the treatment of colorectal cancer

Bär

Pradhan²,

Biersack

et al. 2022

Archiv der Pharmazie

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Colorectal cancer is the third most common cause of cancer-associated deaths due to a high recurrence rate and an increasing occurrence of resistance to established therapies. This highlights the importance of developing new chemotherapeutic agents. The current study focuses on cancer-specific targets such as apoptosisinhibiting survivin, which distinguishes cancer cells from healthy tissue. A combination of pharmacophores of established anticancer agents to afford chimeric pleiotropic chemotherapeutic agents was tested on this cancer entity. We analysed the effects of the dual mode anticancer agents, animthioxam, brimbam, troxbam, and troxham, as well as their structural congeners suberoylanilide hydroxamic acid and combretastatin A-4 on human cancer cell lines. Their cytotoxicity was determined using the MTT assay, further techniques for detecting apoptotic events, cell cycle analyses, clonogenic and wound healing assays, immunostaining, histone deacetylase (HDAC) activity measurements, and Western blot analysis for the detection of survivin expression in HCT116 colon cancer cells. Molecular docking studies were conducted to assess potential molecular targets of the test compounds.The test compounds were found selectively cytotoxic toward cancer cells by inducing apoptosis. The metastatic potential was effectively reduced by disruption of the microtubular cytoskeleton. The test compounds were also proven to be general HDAC inhibitors and to lead to reduced survivin expression.

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Anticancer properties of chimeric HDAC and kinase inhibitors

Cited by 43 publications

References 108 publications

Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors

Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors

Vorinostat (SAHA) and Breast Cancer: An Overview

New chimeric HDAC inhibitors for the treatment of colorectal cancer

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