Publications by authors named "Ulrike Heinicke"

10 Publications

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Nrf2-A Molecular Target for Sepsis Patients in Critical Care.

Biomolecules 2020 12 17;10(12). Epub 2020 Dec 17.

Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Theodor-Stern-Kai 7, 60596 Frankfurt, Germany.

The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with this, data obtained in cell culture experiments and preclinical settings have shown that Nrf2 is important in regulating target genes that are necessary to ensure cellular redox balance. Additionally, Nrf2 is involved in the induction of phase II drug metabolizing enzymes, which are important both in degrading and converting drugs into active forms, and into putative carcinogens. Therefore, Nrf2 has also been implicated in tumorigenesis. This must be kept in mind when new therapy approaches are planned for the treatment of sepsis. Therefore, this review highlights the function of Nrf2 in sepsis with a special focus on the translation of rodent-based results into sepsis patients in the intensive care unit (ICU).
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http://dx.doi.org/10.3390/biom10121688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766194PMC
December 2020

The Emerging Therapeutic Potential of Nitro Fatty Acids and Other Michael Acceptor-Containing Drugs for the Treatment of Inflammation and Cancer.

Front Pharmacol 2020 3;11:1297. Epub 2020 Sep 3.

Department of Safety of Medicinal Products and Medical Devices, Paul-Ehrlich-Institut (Federal Institute for Vaccines and Biomedicines), Langen, Germany.

Nitro fatty acids (NFAs) are endogenously generated lipid mediators deriving from reactions of unsaturated electrophilic fatty acids with reactive nitrogen species. Furthermore, Mediterranean diets can be a source of NFA. These highly electrophilic fatty acids can undergo Michael addition reaction with cysteine residues, leading to post-translational modifications (PTM) of selected regulatory proteins. Such modifications are capable of changing target protein function during cell signaling or in biosynthetic pathways. NFA target proteins include the peroxisome proliferator-activated receptor (PPAR-), the pro-inflammatory and tumorigenic nuclear factor-κB (NF-κB) signaling pathway, the pro-inflammatory 5-lipoxygenases (5-LO) biosynthesis pathway as well as soluble epoxide hydrolase (sEH), which is essentially involved in the regulation of vascular tone. In several animal models of inflammation and cancer, the therapeutic efficacy of well-tolerated NFA has been demonstrated. This has already led to clinical phase II studies investigating possible therapeutic effects of NFA in subjects with pulmonary arterial hypertension. Albeit Michael acceptors feature a broad spectrum of bioactivity, they have for a rather long time been avoided as drug candidates owing to their presumed unselective reactivity and toxicity. However, targeted covalent modification of regulatory proteins by Michael acceptors became recognized as a promising approach to drug discovery with the recent FDA approvals of the cancer therapeutics, afatanib (2013), ibrutinib (2013), and osimertinib (2015). Furthermore, the Michael acceptor, neratinib, a dual inhibitor of the human epidermal growth factor receptor 2 and epidermal growth factor receptor, was recently approved by the FDA (2017) and by the EMA (2018) for the treatment of breast cancer. Finally, a number of further Michael acceptor drug candidates are currently under clinical investigation for pharmacotherapy of inflammation and cancer. In this review, we focus on the pharmacology of NFA and other Michael acceptor drugs, summarizing their potential as an emerging class of future antiphlogistics and adjuvant in tumor therapeutics.
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http://dx.doi.org/10.3389/fphar.2020.01297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495092PMC
September 2020

Angiotensin II treatment in COVID-19 patients: more risk than benefit? A single-center experience.

Crit Care 2020 07 9;24(1):409. Epub 2020 Jul 9.

Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany.

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http://dx.doi.org/10.1186/s13054-020-03143-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347263PMC
July 2020

Histone Deacetylation Inhibitors as Modulators of Regulatory T Cells.

Int J Mol Sci 2020 Mar 29;21(7). Epub 2020 Mar 29.

Fraunhofer-IME, Project Group Translational Medicine and Pharmacology (TMP), 60596 Frankfurt, Germany.

Regulatory T cells (T) are important mediators of immunological self-tolerance and homeostasis. Being cluster of differentiation 4Forkhead box protein3 (CD4FOXP3), these cells are a subset of CD4 T lymphocytes and can originate from the thymus (tT) or from the periphery (pT). The malfunction of CD4 T is associated with autoimmune responses such as rheumatoid arthritis (RA), multiple sclerosis (MS), type 1 diabetes (T1D), inflammatory bowel diseases (IBD), psoriasis, systemic lupus erythematosus (SLE), and transplant rejection. Recent evidence supports an opposed role in sepsis. Therefore, maintaining functional T is considered as a therapy regimen to prevent autoimmunity and allograft rejection, whereas blocking T differentiation might be favorable in sepsis patients. It has been shown that T can be generated from conventional naïve T cells, called iT, due to their induced differentiation. Moreover, T can be effectively expanded in vitro based on blood-derived tT. Taking into consideration that the suppressive role of T has been mainly attributed to the expression and function of the transcription factor Foxp3, modulating its expression and binding to the promoter regions of target genes by altering the chromatin histone acetylation state may turn out beneficial. Hence, we discuss the role of histone deacetylation inhibitors as epigenetic modulators of T in this review in detail.
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http://dx.doi.org/10.3390/ijms21072356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177531PMC
March 2020

BCL-2 selective inhibitor ABT-199 primes rhabdomyosarcoma cells to histone deacetylase inhibitor-induced apoptosis.

Oncogene 2018 09 1;37(39):5325-5339. Epub 2018 Jun 1.

Institute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Komturstr. 3a, 60528, Frankfurt, Germany.

BH3 mimetics are emerging novel anticancer therapeutics that potently and specifically inhibit antiapoptotic BCL-2 proteins and thereby induce cell death in many cancer entities. Previously, we demonstrated that JNJ-26481585 (JNJ), a second-generation histone deacetylase inhibitor (HDACI), engages mitochondrial apoptosis via upregulation of several BH3-only proteins. In the present study, we describe synergistic interactions of JNJ with BH3 mimetics (i.e. ABT-737, ABT-199) in rhabdomyosarcoma (RMS) cells. Importantly, JNJ synergizes with ABT-199 to trigger apoptosis in primary-derived RMS cells isolated from tumor samples, underlining the translational importance of combining these compounds and their potential to improve cancer therapy. Importantly, JNJ/ABT-199 cotreatment also significantly inhibits long-term survival of RMS cells. Mechanistically, JNJ increases expression levels of the BH3-only protein BIM, while exposure to ABT-199 displaces BIM from BCL-2 and shuttles BIM to MCL-1, which also constitutively sequesters NOXA. Both BIM and NOXA contribute to JNJ/ABT-199-mediated cell death, as individual knockdown of NOXA or BIM significantly prevents cell death. Further, JNJ and ABT-199 act in concert to activate BAK and BAX, resulting in loss of the mitochondrial membrane potential (MMP) and caspase activation. These events are required for JNJ/ABT-199-mediated apoptosis, since BAK or BAX silencing or inhibition of caspases significantly protects from JNJ/ABT-199-induced cell death. Rescue experiments demonstrate that overexpression of MCL-1, but not overexpression of BCL-2, blocks JNJ/ABT-199-induced apoptosis. In conclusion, this study provides the first demonstration of ABT-199-induced priming, which sensitizes RMS cells to HDACI, such as JNJ, by engaging mitochondrial apoptosis, highlighting that BH3 mimetics show great promise for the treatment of RMS.
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http://dx.doi.org/10.1038/s41388-018-0212-5DOI Listing
September 2018

BCL-x-selective BH3 mimetic sensitizes rhabdomyosarcoma cells to chemotherapeutics by activation of the mitochondrial pathway of apoptosis.

Cancer Lett 2018 01 23;412:131-142. Epub 2017 Sep 23.

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstrasse 3a, 60528 Frankfurt, Germany; German Cancer Consortium (DKTK), Partner Site Frankfurt, Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

BH3 mimetics are a promising new class of anticancer agents that inhibit antiapoptotic BCL-2 proteins. Here, we report that BH3 mimetics selectively targeting BCL-x, BCL-2 or MCL-1 (i.e. A-1331852, ABT-199, A-1210477) act in concert with multiple chemotherapeutic agents (i.e. vincristine (VCR), etoposide (ETO), doxorubicin, actinomycin D and cyclophosphamide) to induce apoptosis in rhabdomyosarcoma (RMS) cells. Similarly, genetic knockdown of BCL-x primes RMS cells to VCR- or ETO-induced cell death, highlighting the importance of BCL-x in mediating chemotherapy resistance in RMS. A-1331852 and VCR or ETO cooperate to stimulate caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor zVAD.fmk rescues cells from cell death. Molecular studies reveal that VCR/A-1331852 co-treatment causes profound mitotic arrest, which initiates phosphorylation of BCL-2, thereby promoting its inactivation. Also, A-1331852 and VCR or ETO act together to trigger BAX and BAK activation, followed by loss of mitochondrial membrane potential (MMP). Consistently, overexpression of BCL-2 or MCL-1 markedly reduces VCR/A-1331852- or ETO/A-1331852-mediated apoptosis, underscoring that mitochondrial apoptosis represents a key event in synergistic drug interaction. In conclusion, our findings provide a rationale for the combination of BH3 mimetics with conventional chemotherapeutic agents to increase the chemosensitivity of RMS.
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http://dx.doi.org/10.1016/j.canlet.2017.09.025DOI Listing
January 2018

Neuroblastoma cells depend on HDAC11 for mitotic cell cycle progression and survival.

Cell Death Dis 2017 03 2;8(3):e2635. Epub 2017 Mar 2.

Department of Pediatric Hematology, Oncology and SCT, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, Berlin 13353, Germany.

The number of long-term survivors of high-risk neuroblastoma remains discouraging, with 10-year survival as low as 20%, despite decades of considerable international efforts to improve outcome. Major obstacles remain and include managing resistance to induction therapy, which causes tumor progression and early death in high-risk patients, and managing chemotherapy-resistant relapses, which can occur years after the initial diagnosis. Identifying and validating novel therapeutic targets is essential to improve treatment. Delineating and deciphering specific functions of single histone deacetylases in neuroblastoma may support development of targeted acetylome-modifying therapeutics for patients with molecularly defined high-risk neuroblastoma profiles. We show here that HDAC11 depletion in MYCN-driven neuroblastoma cell lines strongly induces cell death, mostly mediated by apoptotic programs. Genes necessary for mitotic cell cycle progression and cell division were most prominently enriched in at least two of three time points in whole-genome expression data combined from two cell systems, and all nine genes in these functional categories were strongly repressed, including CENPA, KIF14, KIF23 and RACGAP1. Enforced expression of one selected candidate, RACGAP1, partially rescued the induction of apoptosis caused by HDAC11 depletion. High-level expression of all nine genes in primary neuroblastomas significantly correlated with unfavorable overall and event-free survival in patients, suggesting a role in mediating the more aggressive biological and clinical phenotype of these tumors. Our study identified a group of cell cycle-promoting genes regulated by HDAC11, being both predictors of unfavorable patient outcome and essential for tumor cell viability. The data indicate a significant role of HDAC11 for mitotic cell cycle progression and survival of MYCN-amplified neuroblastoma cells, and suggests that HDAC11 could be a valuable drug target.
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http://dx.doi.org/10.1038/cddis.2017.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386552PMC
March 2017

JNJ-26481585 primes rhabdomyosarcoma cells for chemotherapeutics by engaging the mitochondrial pathway of apoptosis.

Oncotarget 2015 Nov;6(35):37836-51

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.

Rhabdomyosarcoma (RMS) is a common soft-tissue sarcoma in childhood with a poor prognosis, highlighting the need for new treatment strategies. Here we identify a synergistic interaction of the second-generation histone deacetylase inhibitor (HDACI) JNJ-26481585 and common chemotherapeutic drugs (i.e. Doxorubicin, Etoposide, Vincristine, Cyclophosphamide and Actinomycin D) to trigger apoptosis in RMS cells. Importantly, JNJ-26481585/Doxorubicin cotreatment also significantly suppresses long-term clonogenic survival of RMS cells and tumor growth in vivo in a preclinical RMS model. Mechanistically, JNJ-26481585/Doxorubicin cotreatment causes upregulation of the BH3-only proteins Bim and Noxa as well as downregulation of the antiapoptotic proteins Mcl-1 and Bcl-xL. These changes in the ratio of pro- and antiapoptotic Bcl-2 proteins contribute to JNJ-26481585/Doxorubicin-mediated apoptosis, since knockdown of Bim or Noxa significantly inhibits cell death. Also, JNJ-26481585 and Doxorubicin cooperate to stimulate activation of Bax and Bak, which is required for JNJ-26481585/Doxorubicin-induced apoptosis, since silencing of Bax or Bak protects against apoptosis. Consistently, overexpression of Bcl-2 significantly reduces JNJ-26481585/Doxorubicin-mediated apoptosis. JNJ-26481585/Doxorubicin cotreatment leads to caspase activation and caspase-dependent apoptosis, since the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) rescues cells from apoptosis. In conclusion, the second-generation HDACI JNJ-26481585 cooperates with chemotherapeutics to engage mitochondrial apoptosis in RMS cells, demonstrating that JNJ-26481585 represents a promising strategy for chemosensitization of RMS.
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http://dx.doi.org/10.18632/oncotarget.6097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741969PMC
November 2015

Suberoylanilide hydroxamic acid synergistically enhances the antitumor activity of etoposide in Ewing sarcoma cell lines.

Anticancer Drugs 2015 Sep;26(8):843-51

aDepartment of Pediatric Hematology and Oncology bGerhard-Domagk Institute of Pathology, University Hospital Münster, Münster cInstitute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt dSuabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, Germany.

Ewing sarcomas (ES) are highly malignant tumors arising in bone and soft tissues. Given the poor outcome of affected patients with primary disseminated disease or at relapse, there is a clear need for new targeted therapies. The HDAC inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA, Vorinostat) inhibits ES tumor growth and induces apoptosis in vitro and in vivo. Thus, SAHA may be considered a novel treatment. However, it is most likely that not a single agent but a combination of agents with synergistic mechanisms will help improve the prognosis in high-risk ES patients. Therefore, the aim of the present study was to assess a putative synergistic effect of SAHA in combination with conventional chemotherapeutic agents. The antitumor activity of SAHA in combination with conventional chemotherapeutics (doxorubicin, etoposide, rapamycin, topotecan) was assessed using an MTT cell proliferation assay on five well-characterized ES cell lines (CADO-ES-1, RD-ES, TC-71, SK-ES-1, SK-N-MC) and a newly established ES cell line (DC-ES-15). SAHA antagonistically affected the antiproliferative effect of doxorubicin and topotecan in the majority of the ES cell lines, but synergistically enhanced the antiproliferative activity of etoposide. In functional analyses, pretreatment with SAHA significantly increased the effects of etoposide on apoptosis and clonogenicity. The in-vitro analyses presented in this work show that SAHA synergistically enhances the antitumor activity of etoposide in ES cells. Sequential treatment with etoposide combined with SAHA may represent a new therapeutic approach in ES.
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http://dx.doi.org/10.1097/CAD.0000000000000256DOI Listing
September 2015

Chemosensitization of rhabdomyosarcoma cells by the histone deacetylase inhibitor SAHA.

Cancer Lett 2014 Aug 6;351(1):50-8. Epub 2014 May 6.

Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Komturstr. 3a, 60528 Frankfurt, Germany. Electronic address:

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood with a dismal prognosis, highlighting the need for novel treatment strategies. Here, we identify a novel synthetic lethal interaction between the histone deacetylase inhibitor (HDACI) SAHA and anticancer drugs in RMS cells. Importantly, SAHA significantly increases chemotherapeutic drug-induced apoptosis in both embryonal and alveolar RMS cell lines, including several anticancer agents that are used in the clinic for the treatment of RMS such as Doxorubicin, Etoposide, Vincristine and Cyclophosphamide. Calculation of combination index (CI) reveals that the interaction of SAHA and Doxorubicin or Etoposide is synergistic. Mechanistically, SAHA causes acetylation of histone H3 protein in RMS cells, indicating that SAHA alters the chromatin context. Also, cotreatment with SAHA and Doxorubicin changes the ratio of pro- and antiapoptotic Bcl-2 proteins with downregulation of Mcl-1 and Bcl-xL, dephosphorylation of Bcl-2 and upregulation of BimEL, thus shifting the balance towards apoptosis. Consistently, SAHA and Doxorubicin cooperate to stimulate activation of Bax and Bak, caspase activation and caspase-dependent apoptosis. Overexpression of Bcl-2 significantly rescues SAHA/Doxorubicin-mediated apoptosis, underscoring the requirement of the mitochondrial apoptotic pathway for the synergistic induction of apoptosis by SAHA and Doxorubicin. Caspase-dependent apoptotic cell death is confirmed by the use of the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk), which significantly decreases SAHA/Doxorubicin-triggered apoptosis. In conclusion, these findings demonstrate that the HDACI SAHA represents a promising strategy to prime RMS cells for chemotherapy-induced apoptosis and warrants further investigation in combination regimens.
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http://dx.doi.org/10.1016/j.canlet.2014.04.021DOI Listing
August 2014