Search Results (11)

Background/Objectives: Advanced-stage hepatocellular carcinoma is characterized by a very poor prognosis; thus, highly effective medication is still needed. Often overexpressed heat shock protein 90 is a promising target due to its pivotal role in carcinogenesis. Methods: Antiproliferative effects of 246TMP-3SF5 on HepG2 and HuH-7 cells were assessed by crystal violet staining. Apoptosis was evaluated via subG1 peak, caspase-3 activity and PARP cleavage, and ferroptosis via ROS, glutathione and malondialdehyde levels. Migration was assessed by scratch assay, and in ovo models were used to study angiogenesis and drug effects on microtumors. CAM vascular networks were quantified by semi-automatic segmentation, morphometric and box-counting fractal analysis. Molecular docking and molecular dynamics simulation of heat shock protein 90 were carried out using Autodock Vina and Gromacs respectively. Results: Profound dose- and time-dependent antiproliferative effects of 246TMP-3SF5 against HCC cell lines were observed, revealing low micromolecular IC₅₀ values and selectivity for carcinoma cells with selectivity indices > 1. A significant increase in the sub-G1 peak, key effector caspase-3 activity, as well as cleavage of PARP strongly suggested apoptosis playing a crucial role in the antiproliferative effects. Additionally, HuH-7 cells revealed an elevation of reactive oxygen species and both cell lines showed significant glutathione depletion concomitant with an increase in malondialdehyde concentration upon treatment. The observed effect could be partially reversed by applying ferrostatin-1, suggesting ferroptosis as an additional relevant mode of action. Changes in the cell cycle as well as impaired tumor cell migration were observed. Upon treatment, angiogenesis was impaired and mass of microtumors was significantly reduced. Quantitative CAM analysis showed that vascularized area fraction increased in controls but decreased under both 17-AAG and 246TMP-3SF5. Likewise global mean vessel width decreased relative to controls, while box-counting dimension was reduced under 246TMP-3SF5. Molecular docking and molecular dynamics simulation analysis predicts 246TMP-3SF5 to be binding in catalytic site of heat shock protein 90. Conclusions: 246TMP-3SF5 is a promising novel inhibitor meriting further research as a potential treatment against hepatocellular carcinoma. Full article

Clear cell renal cell carcinoma (ccRCC) is characterized by profound metabolic reprogramming and limited responsiveness to therapeutic stressors, including epigenetic modulation. How glycolytic enzymes contribute to metabolic stress tolerance in ccRCC remains incompletely understood. We investigated the role of the glycolytic enzyme 2,3-bisphosphoglycerate mutase (BPGM) using human tumor specimens, siRNA-mediated gene silencing, functional cell-based assays, and transcriptomic profiling. Epigenetic stress was induced using Vorinostat as a pan-histone deacetylase inhibitor. BPGM expression was consistently elevated in human ccRCC compared with adjacent normal kidney tissue. A498 cells exhibited high basal BPGM levels and limited sensitivity to Vorinostat, whereas BPGM depletion increased cellular stress responses and reduced proliferative capacity. Despite similar phenotypic outcomes, BPGM silencing and Vorinostat treatment triggered distinct transcriptional programs. While HDAC inhibition induced widespread transcriptional changes, BPGM loss elicited a focused stress-associated response, consistent with activation of the unfolded protein response, increased lipid peroxidation, and induction of ER stress-associated genes. Our data identify BPGM as a metabolic player contributing to stress-adaptive transcriptional states in ccRCC and suggest that targeting metabolic stress adaptation may complement epigenetic strategies in renal cancer. Full article

Background/Objectives: New drugs are required for the treatment of liver cancers and protozoal parasite infections. Analogs of the known anticancer active and antileishmanial 2′,4′,6′-trimethoxychalcone SU086 were prepared and investigated. Methods: The chalcones were prepared according to the Claisen–Schmidt condensation protocol and analyzed. They were tested for activity against two liver cancer cell lines (HepG2 and HuH-7) and protozoal parasites (Toxoplasma gondii and Leishmania major). Unspecific toxicity and expression of Hsp90 and Hsp70 upon treatment were analyzed in liver cancer cells. Results: A new chalcone, 2′,4′,6′-trimethoxy-3-pentafluorosulfanylchalcone (246TMP-3SF5), with a pentafluorosulfanyl (SF₅) substituent showed pronounced activities against liver cancer cells and T. gondii parasites which were superior to the activities of the parent chalcone SU086 in these models. In contrast, SU086 and its anthracene analog 2′,4′,6′-trimethoxy-9-anthracenylchalcone (246TMP-Anth) were most active against L. major promastigotes. The new SF₅-substituted chalcone behaved like the known Hsp90 inhibitor 17-AAG and upregulated Hsp70 expression in liver cancer cells. Conclusions: The SF₅-substituted SU086 analog has potential to become a new drug for the therapy of hepatoma and toxoplasmosis. Full article

A class of chaperones dubbed heat shock protein 70 (Hsp70) possesses high relevance in cancer diseases due to its cooperative activity with the well-established anticancer target Hsp90. However, Hsp70 is closely connected with a smaller heat shock protein, Hsp40, forming a formidable Hsp70-Hsp40 axis in various cancers, which serves as a suitable target for anticancer drug design. This review summarizes the current state and the recent developments in the field of (semi-)synthetic small molecule inhibitors directed against Hsp70 and Hsp40. The medicinal chemistry and anticancer potential of pertinent inhibitors are discussed. Since Hsp90 inhibitors have entered clinical trials but have exhibited severe adverse effects and drug resistance formation, potent Hsp70 and Hsp40 inhibitors may play a significant role in overcoming the drawbacks of Hsp90 inhibitors and other approved anticancer drugs. Full article

New N-alkylindole-substituted 2-(pyrid-3-yl)-acrylonitriles with putative kinase inhibitory activity and their (p-cymene)Ru(II) piano-stool complexes were prepared and tested for their antiproliferative efficacy in various cancer models. Some of the indole-based derivatives inhibited tumor cell proliferation at (sub-)micromolar concentrations with IC₅₀ values below those of the clinically relevant multikinase inhibitors gefitinib and sorafenib, which served as positive controls. A focus was set on the investigation of drug mechanisms in HCT-116 p53-knockout colon cancer cells in order to evaluate the dependence of the test compounds on p53. Colony formation assays as well as experiments with tumor spheroids confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic caspase-3/7 activity and ROS formation, as well as anti-angiogenic properties. Docking calculations with EGFR and VEGFR-2 identified the two 3-aryl-2-(pyrid-3-yl)acrylonitrile derivatives 2a and 2b as potential kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in cancer treatment. Full article

The surfactant protein-G (SP-G) has recently been discovered in the brain and linked to fluid balance regulations. Stroke is characterized by impaired vessel integrity, promoting water influx and edema formation. The neurovascular unit concept (NVU) has been generated to cover not only ischemic affections of neurons or vessels but also other regionally associated cells. This study provides the first spatio-temporal characterization of SP-G and NVU elements after experimental stroke. Immunofluorescence labeling was applied to explore SP-G, vascular and cellular markers in mice (4, 24, and 72 h of ischemia), rats (24 h of ischemia), and sheep (two weeks of ischemia). Extravasated albumin indicated vascular damage within ischemic areas. Quantifications revealed decreasing SP-G signals in the ischemia-affected neocortex and subcortex. Inverse immunosignals of SP-G and vascular elements existed throughout all models. Despite local associations between SP-G and the vasculature, a definite co-localization was not seen. Along with a decreased SP-G-immunoreactivity in ischemic areas, signals originating from neurons, glial elements, and the extracellular matrix exhibited morphological alterations or changed intensities. Collectively, this study revealed regional alterations of SP-G, vascular, and non-vascular NVU elements after ischemia, and may thus stimulate the discussion about the role of SP-G during stroke. Full article

New medical treatments are urgently needed for advanced hepatocellular carcinoma (HCC). Recently, we showed the anticancer effects of novel thiophene-based kinase inhibitors. In this study, we further characterized the antineoplastic effects and modes of action of the two most promising inhibitors, Thio-Iva and Thio-Dam, and compared their effects with the clinically relevant multi-kinase inhibitor, sorafenib, in HCC cells. Crystal violet staining and real-time cell growth monitoring showed pronounced antiproliferative effects in Huh-7 and SNU-449 cells with IC₅₀ values in the (sub-)micromolar range. Long-term incubation experiments revealed the reduced clonogenicity of Thio-Iva and Thio-Dam-treated HCC cells. LDH-release tests excluded cytotoxicity as an unspecific mode of action of the inhibitors, while flow cytometry analysis revealed a dose-dependent and pronounced G2/M phase cell cycle arrest and cyclin B1 suppression. Additionally, mitochondria-driven apoptosis was observed through the cytosolic increase of reactive oxygen species, a concomitant PARP cleavage, and caspase-3 induction. Both compounds were found to effectively inhibit the capillary tube formation of endothelial EA.hy926 cells in vitro, pointing towards additional antiangiogenic effects. Antiangiogenic and antineoplastic effects were confirmed in vivo by CAM assays. In summary, the thienyl-acrylonitrile derivatives, Thio-Iva and Thio-Dam, exert significant antineoplastic and antiangiogenic effects in HCC cells. Full article

The development of new anticancer drugs is necessary in order deal with the disease and with the drawbacks of currently applied drugs. Epigenetic dysregulations are a central hallmark of cancerogenesis and histone deacetylases (HDACs) emerged as promising anticancer targets. HDAC inhibitors are promising epigenetic anticancer drugs and new HDAC inhibitors are sought for in order to obtain potent drug candidates. The new HDAC inhibitor SF5-SAHA was synthesized and analyzed for its anticancer properties. The new compound SF5-SAHA showed strong inhibition of tumor cell growth with IC₅₀ values similar to or lower than that of the clinically applied reference compound vorinostat/SAHA (suberoylanilide hydroxamic acid). Target specific HDAC inhibition was demonstrated by Western blot analyses. Unspecific cytotoxic effects were not observed in LDH-release measurements. Pro-apoptotic formation of reactive oxygen species (ROS) and caspase-3 activity induction in prostate carcinoma and hepatocellular carcinoma cell lines DU145 and Hep-G2 seem to be further aspects of the mode of action. Antiangiogenic activity of SF5-SAHA was observed on chorioallantoic membranes of fertilized chicken eggs (CAM assay). The presence of the pentafluorothio-substituent of SF5-SAHA increased the antiproliferative effects in both solid tumor and leukemia/lymphoma cell models when compared with its parent compound vorinostat. Based on this preliminary study, SF5-SAHA has the prerequisites to be further developed as a new HDAC inhibitory anticancer drug candidate. Full article

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. Full article

New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC₅₀ values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment. Full article

Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa. Full article