Diana Groza
Medical University of Vienna
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by Diana Groza.
Chemical Communications | 2013
Verena Pichler; Josef Mayr; Petra Heffeter; Orsolya Dömötör; Éva A. Enyedy; Gerrit Hermann; Diana Groza; Gunda Köllensperger; Markus Galanksi; Walter Berger; Bernhard K. Keppler; Christian R. Kowol
Maleimide-functionalised Pt(IV) complexes with highly selective binding properties to thiol groups were synthesised as precursors for binding of thiol-containing tumour-targeting molecules like human serum albumin.
European Journal of Cancer | 2013
Petra Heffeter; Bihter Atil; Kushtrim Kryeziu; Diana Groza; Gunda Koellensperger; Wilfried Körner; Ute Jungwirth; Thomas Mohr; Bernhard K. Keppler; Walter Berger
KP1339 is a promising ruthenium-based anticancer compound in early clinical development. This study aimed to test the effects of KP1339 on the in vitro and in vivo activity of the multi-kinase inhibitor sorafenib, the current standard first-line therapy for advanced hepatoma. Anticancer activity of the parental compounds as compared to the drug combination was tested against a panel of cancer cell lines with a focus on hepatoma. Combination of KP1339 with sorafenib induced in the majority of all cases distinctly synergistic effects, comprising both sorafenib-resistant as well as sorafenib-responsive cell models. Several mechanisms were found to underlie these multifaceted synergistic activities. Firstly, co-exposure induced significantly enhanced accumulation levels of both drugs resulting in enhanced apoptosis induction. Secondly, sorafenib blocked KP1339-mediated activation of P38 signalling representing a protective response against the ruthenium drug. In addition, sorafenib treatment also abrogated KP1339-induced G2/M arrest but resulted in check point-independent DNA-synthesis block and a complete loss of the mitotic cell populations. The activity of the KP1339/sorafenib combination was evaluated in the Hep3B hepatoma xenograft. KP1339 monotherapy led to a 2.4-fold increase in life span and, thus, was superior to sorafenib, which induced a 1.9-fold prolonged survival. The combined therapy further enhanced the mean survival by 3.9-fold. Synergistic activity was also observed in the VM-1 melanoma xenograft harbouring an activating braf mutation. Together, our data indicate that the combination of KP1339 with sorafenib displays promising activity in vitro and in vivo especially against human hepatoma models.
Angewandte Chemie | 2014
Claudia Karnthaler‐Benbakka; Diana Groza; Kushtrim Kryeziu; Verena Pichler; Alexander Roller; Walter Berger; Petra Heffeter; Christian R. Kowol
The development of receptor tyrosine-kinase inhibitors (TKIs) was a major step forward in cancer treatment. However, the therapy with TKIs is limited by strong side effects and drug resistance. The aim of this study was the design of novel epidermal growth factor receptor (EGFR) inhibitors that are specifically activated in malignant tissue. Thus, a Co(III) -based prodrug strategy for the targeted release of an EGFR inhibitor triggered by hypoxia in the solid tumor was used. New inhibitors with chelating moieties were prepared and tested for their EGFR-inhibitory potential. The most promising candidate was coupled to Co(III) and the biological activity tested in cell culture. Indeed, hypoxic activation and subsequent EGFR inhibition was proven. Finally, the compound was tested in vivo, also revealing potent anticancer activity.
Pharmacological Research | 2017
Maria Laura Pati; Diana Groza; Chiara Riganti; Joanna Kopecka; Mauro Niso; Francesco Berardi; Sonja Hager; Petra Heffeter; Miwa Hirai; Hitoshi Tsugawa; Yasuaki Kabe; Makoto Suematsu; Carmen Abate
Graphical abstract Figure. No Caption available. Abstract A controversial relationship between sigma‐2 and progesterone receptor membrane component 1 (PGRMC1) proteins, both representing promising targets for the therapy and diagnosis of tumors, exists since 2011, when the sigma‐2 receptor was reported to be identical to PGRMC1. Because a misidentification of these proteins will lead to biased future research hampering the possible diagnostic and therapeutic exploitation of the two targets, there is the need to solve the debate on their identity. With this aim, we have herein investigated uptake and distribution of structurally different fluorescent sigma‐2 receptor ligands by flow cytometry and confocal microscopy in MCF7 cells, where together with intrinsic sigma‐2 receptors, PGRMC1 was constitutively present or alternatively silenced or overexpressed. HCT116 cells, with constitutive or silenced PGRMC1, were also studied. These experiments showed that the fluorescent sigma‐2 ligands bind to their receptor irrespective of PGRMC1 expression. Furthermore, isothermal titration calorimetry was conducted to examine if DTG and PB28, two structurally distinct nanomolar affinity sigma‐2 ligands, bind to purified PGRMC1 proteins that have recently been revealed to form both apo‐monomeric and heme‐mediated dimeric forms. While no binding to apo‐PGRMC1 monomer was detected, a micromolar affinity to heme‐mediated dimerized PGRMC1 was demonstrated in DTG but not in PB28. The current data provide evidence that sigma‐2 receptor and PGRMC1 are not identical, paving the pathway for future unbiased research in which these two attractive targets are treated as different proteins while the identification of the true sigma‐2 protein further needs to be pursued.
Molecular Pharmaceutics | 2017
Maria Laura Pati; Elisabetta Fanizza; Sonja Hager; Diana Groza; Petra Heffeter; Amelita Grazia Laurenza; Valentino Laquintana; M. L. Curri; Nicoletta Depalo; Carmen Abate; Nunzio Denora
The increasing importance of sigma-2 receptor as target for the diagnosis and therapy of tumors paves the way for the development of innovative optically traceable fluorescent probes as tumor cell contrast and therapeutic agents. Here, a novel hybrid organic-inorganic nanostructure is developed by combining the superior fluorescent properties of inorganic quantum dots (QDs), coated with a hydrophilic silica shell (QD@SiO2 NPs), the versatility of the silica shell, and the high selectivity for sigma-2 receptor of the two synthetic ligands, namely, the 6-[(6-aminohexyl)oxy]-2-(3-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)propyl)-3,4-dihydroisoquinolin-1(2H)-one (MLP66) and 6-[1-[3-(4-cyclohexylpiperazin-1-yl)propyl]-1,2,3,4-tetrahydronaphthalen-5-yloxy]hexylamine (TA6). The proposed nanostructures represent a challenging alternative to all previously studied organic small fluorescent molecules, based on the same sigma-2 receptor affinity moieties. Flow cytometry and confocal fluorescence microscopy experiments, respectively, on fixed and living cancerous MCF7 cells, which overexpress the sigma-2 receptor, prove the ability of functionalized (QD@SiO2-TA6 and QD@SiO2-MLP66) NPs to be internalized and demonstrate their affinity to the sigma-2 receptor, ultimately validating the targeting properties conveyed to the NPs by sigma-2 ligand conjugation. The presented QD-based nanoprobes possess a great potential as in vitro selective sigma-2 receptor imaging agent and, consequently, could provide a significant impact to future theranostic applications.
ChemMedChem | 2016
Claudia Karnthaler‐Benbakka; Diana Groza; Bettina Koblmüller; Alessio Terenzi; Katharina Holste; Melanie Haider; Dina Baier; Walter Berger; Petra Heffeter; Christian R. Kowol; Bernhard K. Keppler
Tyrosine kinase inhibitors (TKIs), which have revolutionized cancer therapy over the past 15 years, are limited in their clinical application due to serious side effects. Therefore, we converted two approved TKIs (sunitinib and erlotinib) into 2‐nitroimidazole‐based hypoxia‐activatable prodrugs. Kinetics studies showed very different stabilities over 24 h; however, fast reductive activation via E. coli nitroreductase could be confirmed for both panels. The anticancer activity and signaling inhibition of the compounds against various human cancer cell lines were evaluated in cell culture. These data, together with molecular docking simulations, revealed distinct differences in the impact of structural modifications on drug binding to the enzymes: whereas the catalytic pocket of the epidermal growth factor receptor (EGFR) accepted all new erlotinib derivatives, the vascular endothelial growth factor receptor (VEGFR)‐inhibitory potential in the case of the sunitinib prodrugs was dramatically diminished by derivatization. In line, hypoxia dependency of ERK signaling inhibition was observed with the sunitinib prodrugs, while oxygen levels had no impact on the activity of the erlotinib derivatives. Overall, proof of principle could be shown for this concept, and the results obtained are an important basis for the future development of tyrosine kinase inhibitor prodrugs.
OncoImmunology | 2018
Diana Groza; Sebastian Gehrig; Pavol Kudela; Martin Holcmann; Christine Pirker; Carina Dinhof; Hemma H. Schueffl; Marek Sramko; Julia Hoebart; Fatih Alioglu; Michael Grusch; Manfred Ogris; Werner Lubitz; Bernhard K. Keppler; Irena Pashkunova-Martic; Christian R. Kowol; Maria Sibilia; Walter Berger; Petra Heffeter
ABSTRACT Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistance – often due to insufficient drug delivery – is still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gram-negative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune-adjuvant to chemotherapy in advanced CRC.
Archive | 2016
Josef Mayr; Petra Heffeter; Diana Groza; Luis Galvez; Gunda Koellensperger; Alexander Roller; Beatrix Alte; Melanie Haider; Walter Berger; Christian R. Kowol; Bernhard K. Keppler
Related Article: Josef Mayr, Petra Heffeter, Diana Groza, Luis Galvez, Gunda Koellensperger, Alexander Roller, Beatrix Alte, Melanie Haider, Walter Berger, Christian R. Kowol, Bernhard K. Keppler|2017|Chemical Science|8|2241|doi:10.1039/C6SC03862J
Cancer Research | 2015
Petra Heffeter; Claudia Karnthaler‐Benbakka; Diana Groza; Kushtrim Kryeziu; Walter Berger; Bernhard K. Keppler; Christian R. Kowol
Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Chemotherapy and therapy with small targeted molecules are two major strategies for therapy of human cancer at the disseminated stage. During the last decades, thousands of compounds have been developed and, consequently, have improved therapy effectiveness. Especially the development of receptor tyrosine kinase inhibitors such as erlotinib or imatinib were major step forwards in cancer treatment. However, despite its success EGFR inhibitor therapy is still limited by strong side effects, resistance development and insufficient tumor accumulation. Aim of the here presented study was the development of novel EGFR inhibitors, which are specifically activated in the malignant tissue. To this end a cobalt(III)-based prodrug strategy was used, which allows targeted release of the active EGFR inhibitor triggered by hypoxic conditions of the solid tumor. As a first step, new inhibitors with bis-chelating moieties were prepared and tested for their efficacy against several cell models with differing EGFR status. The most promising lead candidate was selected based on potent kinase inhibition (confirmed by in vitro kinase assays as well as Western blotting) resulting in activity against EGFR-driven cells in the nM range (MTT assay). Subsequently, the respective cobalt complex was prepared and its activity tested in hypoxia vs. normoxia revealing that the new complex was distinctly more active under hypoxic conditions. Finally, the anticancer activity of the new complex was tested in two xenografts indicationg potent and hypoxia-dependent anticancer activity also in vivo. Summarizing, cobalt(III)-based tumor-targeting represents a promising strategy to reduce the side effects of tyrosine kinase inhibitors such as erlotinib. Acknowledgements. This work was performed in course of the research platform “Translational Cancer Therapy Research” Vienna, Austria and the COST action CM1105 and supported by “Fonds der Stadt Wien fur innovative interdisziplinare Krebsforschung”. Citation Format: Petra Heffeter, Claudia Karnthaler-Benbakka, Diana Groza, Kushtrim Kryeziu, Walter Berger, Bernhard K. Keppler, Christian R. Kowol. Preclinical development of a novel hypoxia-activated EGFR inhibitor using a cobalt(III)-based prodrug design. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4397. doi:10.1158/1538-7445.AM2015-4397
Chemical Science | 2017
Josef Mayr; Petra Heffeter; Diana Groza; Luis Galvez; Gunda Koellensperger; Alexander Roller; Beatrix Alte; Melanie Haider; Walter Berger; Christian R. Kowol; Bernhard K. Keppler