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Background: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of Endoplasmic Reticulum (ER) stress and subsequent activation of the Unfolded Protein Response (UPR) has been proposed as a potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis. Objective: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives. Methods: Cell proliferation assays were performed on HeLa, Capan-1, MCF-7, HCC-1937, and MRC-5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis. Results: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of pro-apoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and -7. The flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells). Conclusion: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways., Scientific and Technical Research Council of Turkey (TUBITAK) Research Fund [215S112], This study was supported by the Scientific and Technical Research Council of Turkey (TUBITAK) Research Fund under project number 215S112.

Purpose Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide with. lack of effective systemic chemotherapy. In this study, we aimed to evaluate the value of ATPase family AAA domain-containing protein 2 (ATAD2) as a biomarker and potential therapeutic target for HCC. Methods The expression of ATAD2 was tested in different HCC patient cohorts by immunohistochemistry and comparative transcriptional analysis. The co-expression of ATAD2 and proliferation markers was compared during liver regeneration and malignancy with different bioinformatics tools. The cellular effects of ATAD2 inactivation in liver malignancy was tested on cell cycle, apoptosis and colony formation ability as well as tumor formation using RNA interference. The genes affected by ATAD2 inactivation in three different HCC cell lines were identified by global gene expression profiling and bioinformatics tools. Results ATAD2 is overexpression is closely correlated with HCC tumor stage. There was gradual increase from dysplasia, well differentiated and poorly differentiated HCC, respectively. We also observed transient upregulation of ATAD2 expression during rat liver regeneration in parallel to changes in Ki-67 expression. ATAD2 knockdown resulted in apoptosis and decreased cell survival in vitro and decreased tumor formation in some HCC cell lines. However, three other HCC cell lines tested where not affected. Similarly, gene expression response to ATAD2 inactivation in different HCC cell lines was highly heterogeneous. Conclusions ATAD2 is a potential proliferation marker for liver regeneration and HCC. It may also serve as a therapeutic target despite heterogeneous response of malignant cells.

A series of novel N-aryl-1-(4-sulfamoylphenyl)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxamides was synthesized and examined as inhibitors of cytosolic (human) hCA I and hCA II, and cancer-related transmembrane hCA IX and hCA XII isoenzymes. AC2 was the most selective inhibitor towards cancer-related hCA IX while AC8 and AC9 selectively inhibited hCA XII over off-target isoenzymes. Anticancer effects of the compounds were evaluated towards human oral squamous cell carcinoma (OSCC) cell lines, human mesenchymal normal oral cells, breast (MCF7), prostate (PC3), non-small cell lung carcinoma cells (A549), and non-tumoral fetal lung fibroblast cells (MRC5). Compounds moderately showed cytotoxicity towards cancer cell lines. Among others, AC6 showed cell specific cytotoxic activity and induced apoptosis in a dose-dependent manner without a significant change in the cell cycle distribution of MCF7. These results suggest that pyrazole-3-carboxamides need further molecular modification to increase their anticancer drug candidate potency., Scientific and Technological Research Council of Turkey (TUBITAK) [219S076], We gratefully acknowledge financial support from The Scientific and Technological Research Council of Turkey (TUBITAK, Project no: 219S076) .

A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and anti-proliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, beta 1 subunit), trypsin-like (T-L, beta 2 subunit) and chymotrypsin-like (ChT-L, beta 5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC50 values of 9.90 +/- 0.61, 44.83 +/- 4.23 and 22.27 +/- 0.15 mu M against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC50 = 12.47 +/- 0.21, 53.12 +/- 2.56 and 26.37 +/- 0.5 mu M), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC50 = 1.72 +/- 0.14-20.8 +/- 0.5 mu M and compounds 13 and 28 were found to be the most active compounds with IC50 values of 1.79 +/- 0.21 and 1.72 +/- 0.14 mu M, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions. (c) 2020 Elsevier Masson SAS. All rights reserved., Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [116S300]; Ege UniversityEge University [14ECZ042], This study was supported by grants from The Scientific and Technological Research Council of Turkey (TUBITAK, Project Number:116S300) and Ege University (Project Number: 14ECZ042). The authors thank also to the Pharmaceutical Sciences Research Centre (FABAL) at Ege University, Faculty of Pharmacy for spectral and elemental analyses of the compounds.

Proteostasis regulates key cellular processes such as cell proliferation, differentiation, transcription, and apoptosis. the mechanisms by which proteostasis is regulated are crucial and the deterioration of cellular proteostasis has been significantly associated with tumorigenesis since it specifically targets key oncoproteins and tumor suppressors. Prostate cancer (PCa) is the second most common cause of cancer death in men worldwide. Androgens mediate one of the most central signaling pathways in all stages of PCa via the androgen receptor (AR). in addition to their regulation by hormones, PCa cells are also known to be highly secretory and are particularly prone to ER stress as proper ER function is essential. Alterations in various complex signaling pathways and cellular processes including cell cycle control, transcription, DNA repair, apoptosis, cell adhesion, epithelial-mesenchymal transition (EMT), and angiogenesis are critical factors influencing PCa development through key molecular changes mainly by posttranslational modifications in PCa-related proteins, including AR, NKX3.1, PTEN, p53, cyclin D1, and p27. Several ubiquitin ligases like MDM2, Siah2, RNF6, CHIP, and substrate-binding adaptor SPOP; deubiquitinases such as USP7, USP10, USP26, and USP12 are just some of the modifiers involved in the regulation of these key proteins via ubiquitin-proteasome system (UPS). Some ubiquitin-like modifiers, especially SUMOs, have been also closely associated with PCa. on the other hand, the proteotoxicity resulting from misfolded proteins and failure of ER adaptive capacity induce unfolded protein response (UPR) that is an indispensable signaling mechanism for PCa development. Lastly, ER-associated degradation (ERAD) also plays a crucial role in prostate tumorigenesis. in this section, the relationship between prostate cancer and proteostasis will be discussed in terms of UPS, UPR, SUMOylation, ERAD, and autophagy., Scientific and Technological Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [SBAG-108S056/114S062]; Ege University internal funds; BAGEP Award of the Science Academy; Pfizer-TurkeyPfizer; COST Action (PROTEOSTASIS)European Cooperation in Science and Technology (COST) [BM1307]; COST (European Cooperation in Science and Technology)European Cooperation in Science and Technology (COST), Work by PBK is supported by the Scientific and Technological Research Council of Turkey (TUBITAK, SBAG-108S056/114S062), Ege University internal funds, BAGEP Award of the Science Academy with funding supplied by Pfizer-Turkey, COST Action (PROTEOSTASIS BM1307), and by COST (European Cooperation in Science and Technology).

PubMed: 31059704 Polyether compounds, a large group of biologically active metabolites produced by Streptomyces species have been reported to show a variety of bioactivity such as antibacterial, antifungal, antiparasitic, antiviral, and tumour cell cytotoxicity. Since some of these compounds target cancer stem cells and multi-drug resistant cancer cells, this family of compounds have become of high interest. In this study, three polyether-type metabolites (1–3), one of which was a new natural product (3), were isolated from the marine derived Streptomyces cacaoi via antimicrobial activity-guided fractionation studies. As several polyether compounds with structural similarity such as monensin have been linked with autophagy and cell death, we first assessed the cytotoxicity of these three compounds. Compounds 2 and 3, but not 1, were found to be cytotoxic in several cell lines with a higher potency towards cancer cells. Furthermore, 2 and 3 caused accumulation of both autophagy flux markers LC3-II and p62 along with cleavage of caspase-3, caspase-9 and poly (ADP-ribose)polymerase 1 (PARP-1). Interestingly, prolonged treatment of the compounds caused a dramatic downregulation of the proteins related to autophagasome formation in a dose dependent manner. Our findings provide insights on the molecular mechanisms of the polyether-type polyketides, and signify their potency as chemotherapeutic agents through inhibiting autophagy and inducing apoptosis. © 2019 Elsevier B.V. 2012/BİL/028 109S361 This research was supported by grants from TUBITAK (109S361) and EBILTEM (2012/BİL/028) (E.B.).

Poly (ADP-ribose) polymerase (PARP) enzyme catalyzes the transfer of ADP-ribose into target proteins. Therefore, PARP is responsible for DNA repair, cell proliferation, and cell death. In this study, potential PARP enzyme inhibitors were designed and synthesized. The synthesized compounds were elucidated by Fourier-transform infrared spectroscopy, 1 H NMR, 13 C NMR, heteronuclear single-quantum correlation, and mass spectrometry, and their purity was checked via thin-layer chromatography, high-performance liquid chromatography, and elemental analysis. A total of 63 newly synthesized compounds were screened in terms of PARP inhibition by cellular PARylation assay in the HeLa cell line. It was found that 19 compounds significantly inhibited the H 2 O 2 -induced cellular PARylation. The chemosensitizer effect of these compounds in cancer cells treated with doxorubicin (doxo) was investigated. It was found that the combination of potent PARP inhibitors with doxo potentiated a cytotoxic effect, similar to that of olaparib. The results of the molecular docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis revealed that compound 60 might be classified as a potential PARP inhibitor candidate. Taken together, all of the results suggested that carbohydrazide derivatives could be a promising lead for the treatment for cancer disorders. © TÜBİTAK SAG-C-DRP-100616-0260 Türkiye Bilimsel ve Teknolojik Araştirma Kurumu, TÜBITAK 215S112 This study was supported by the Scientific and Technical Research Council of Turkey (TÜBİTAK) Research Fund under project number: 215S112 and the Marmara University Scientific Research Commission under grant number: SAG-C-DRP-100616-0260.

Isatin, 1H-indoline-2,3-dione, an endogenous compound, is also a synthetically versatile molecule that possesses a diversity of biological activities including anticonvulsant, antibacterial, antifungal, antiviral, anticancer, and cytotoxic properties. Based on the promising cytotoxic activity studies on N-substituted isatin derivatives, a series of 18 derivatives of 2-(2,3-dioxo-2,3-dihydro- 1H-indol-1-yl)-N-phenylacetamide were designed, synthesized, and characterized according to their analytical and spectral data. All of the compounds were evaluated for their cytotoxic activity against MCF7, A549, HeLa, and HEK293 cell lines by real time cell analyzer. Etoposide was used as a standard compound. Briefly, ortho substitutions gave better results compared to meta and para substitutions on the N-phenyl ring and compounds bearing ortho substitutions were more effective on MCF7 cell lines than A549 and HeLa cell lines. 2-(2,3-Dioxo-2,3-dihydro-1H-indol-1-yl)-N- (2-isopropylphenyl)acetamide was the most active compound against all the tested cell lines.